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Inheritance

1

Autosomal dominant HP:0000006

Three affected individuals in two unrelated families all carry the same heterozygous MIR140 substitution. It arose de novo in the two probands and was transmitted from an affected mother to her affected son. Dominance here is not haploinsufficiency: a heterozygous MIR140 deletion has not been associated with skeletal disease in humans and heterozygous miR-140 knockout mice are normal, so it is the presence of the mutant microRNA product, not the absence of half the wild-type dose, that produces the phenotype.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"The same single nucleotide substitution occurred de novo in P1 and P3, and co-segregated with the skeletal dysplasia phenotype in Family 1"

Both halves of the dominant argument in one sentence: two independent de novo events on the same nucleotide, and vertical segregation in the family that has two affected members.

PMID:30804514 SUPPORT Human Clinical

"This result suggests that haploinsufficiency of MIR140 does not lead to skeletal abnormalities in humans, consistent with the normal phenotype previously reported in heterozygous miR-140 knockout mice6, supporting the hypothesis that the heterozygous nucleotide substitution (chr16:g.69967007A>G..."

The CNV-database search that rules out simple haploinsufficiency as the basis of the dominance, and the mouse result that agrees with it.

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Mechanistic Hypotheses

1

TRPS1 repression by the mutant seed as the route to cone-shaped epiphyses

trps1_cone_epiphysis_bridge EMERGING

Evidence balance 2 support

A candidate bridge between one named acquired target and one specific patient feature. TRPS1 is among the genes the mutant miR-140-5p seed acquires as targets, and heterozygous TRPS1 loss of function causes trichorhinophalangeal syndrome, whose diagnostic radiographic finding is cone-shaped epiphyses - which is also one of the radiological hallmarks of this disorder. If the mutant microRNA represses TRPS1 in patient chondrocytes, that would be a single-target explanation for a phenotype that otherwise has to be attributed to a diffuse transcriptional shift. It is recorded as EMERGING rather than curated as an established edge because the founding paper names Trps1 in a list of acquired targets and does not attribute any patient feature to it. Nobody has measured TRPS1 in a miR-140 mutant chondrocyte, in a patient, or in a reporter assay against the TRPS1 3-prime UTR, and no epistasis experiment has been done. The two disorders also differ in almost everything else: trichorhinophalangeal syndrome has sparse hair, dystrophic nails and a distinctive nose, none of which is reported here, so if the bridge holds it is partial rather than a shared mechanism.

Pathograph links

Repression of Novel Targets Acquired by the Mutant Seed -> Cone-Shaped Phalangeal Epiphyses INDIRECT UNKNOWN INTERMEDIATES A hypothesis-tagged edge, not an established one. It exists only under the trps1_cone_epiphysis_bridge hypothesis, which proposes that repression of the acquired target TRPS1 is what produces the cone-shaped epiphyses. Read the hypothesis before reading this edge; the intermediates are not known and the target has not been measured in this disease.

Show evidence (2 references)

PMID:30804514 SUPPORT INDIRECT In Vitro

"The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways"

The half of the hypothesis that is established: Trps1 is among the transcripts the mutant seed acquires. The paper goes no further than naming it.

PMID:28426188 SUPPORT INDIRECT Other

"The clinical diagnosis of TRPS can be established in a proband with characteristic facial features, ectodermal and joint manifestations, and skeletal findings of cone-shaped epiphyses."

The other half: cone-shaped epiphyses are the radiographic hallmark of the TRPS1 disease, which is what makes the acquired target interesting. Graded OTHER because a GeneReviews chapter is an expert synthesis rather than a study reporting its own data, and INDIRECT because it is about a different disorder.

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Discussions and Knowledge Gaps

3

Does the mutant seed repress the same transcripts in a human chondrocyte that it represses in a mouse one, and does a patient growth plate have the expanded resting zone?

KNOWLEDGE GAP OPEN sedn_no_human_tissue

Attached to

pathophysiology#Repression of Novel Targets Acquired by the Mutant Seed pathophysiology#Resting-Zone Chondrocyte Expansion

Every mechanistic measurement in this entry was made in mouse cells or mouse bone. That is not a criticism of the work - the knock-in carries the patients' exact substitution and the mature miR-140-5p sequence is conserved - but it leaves two specific things unmeasured in humans, and they are not the same kind of gap. The acquired target set is the first. It was predicted by TargetScan and confirmed against the mouse transcriptome. Because the seed is newly created, its targets have no evolutionary history with it, so there is no reason to expect the 3-prime UTR matches to be conserved between mouse and human the way the wild-type target set is - the founding study itself reports that mutant-seed target sites are less conserved than wild-type ones. A human chondrocyte could therefore carry a materially different acquired target set from the mouse. Nothing about that has been tested. The resting-zone expansion is the second, and it is a gap of a different kind: no human growth plate from a patient has been examined at all. The human evidence is radiographic delay in ossification, which is compatible with the mouse lesion but does not demonstrate it. Since the resting-zone phenotype is what the entire metabolic branch was built to explain, its human status matters more than its position in the entry suggests. Neither gap can be closed with the existing patients without cartilage, which is not ordinarily biopsied. Patient-derived induced pluripotent stem cells differentiated to chondrocytes would answer the first question and are within reach; the second may not be answerable at all outside an incidental surgical specimen.

Show evidence (1 reference)

PMID:30804514 SUPPORT In Vitro

"Target sites of miR-140-5p-G seldom overlapped with those of wild-type miR-140 species (wild-type 5p, 3p.1, and 3p.2) and were less conserved than those of wild-type miR-140 species"

The specific reason the mouse acquired target set may not transfer: those sites are the less conserved ones, so cross-species inference is weaker here than for the wild-type set.

Does reduced acetyl-CoA in miR-140 mutant chondrocytes cause the resting-zone expansion, and does it do so by raising FGFR3?

OPEN QUESTION OPEN sedn_metabolic_branch_is_provisional

Attached to

pathophysiology#Reduced Acetyl-CoA Availability and Histone Acetylation pathophysiology#Resting-Zone Chondrocyte Expansion

The metabolic branch of this entry is attractive and incompletely demonstrated, and it is worth being exact about which links are which. Measured in the miR-140 mutant itself: HIF1A falls, glycolytic gene expression falls, mitochondrial gene expression rises, the Seahorse assay confirms the reciprocal shift, and histone acetylation falls. Measured in surrogates: that suppressing glycolysis by deleting Ldha, or blocking acetyl-CoA synthesis by deleting Acly, expands the resting zone and increases resting chondrocyte proliferation. The Acly result is the good control, because it separates acetyl-CoA from ATP supply, which a glycolysis block alone would not. What has not been done is the experiment in the middle: nobody has restored acetyl-CoA in a miR-140 mutant and asked whether the resting zone normalises. Until that is done, the identity of the mechanism in the mutant with the mechanism in the knockouts is an inference from phenotypic similarity. The onward step to FGFR3 is weaker again and is deliberately not curated as a causal edge. Fgfr3 is upregulated in both knockouts and a constitutively active FGFR3 expands the resting zone, which makes it a good candidate, but the authors write that the mechanism by which acetyl-CoA deficiency would raise Fgfr3 is not clear, and no chromatin measurement at the Fgfr3 locus has been reported. A causal edge here would assert more than the source does. It is also worth noting the irony that would follow if it held: an FGFR3 gain of signalling is the mechanism of achondroplasia, reached in this disease by an entirely different route. A further caveat applies to the whole branch. Its source is a bioRxiv preprint that had not appeared in a peer-reviewed journal as of curation, and it has not been independently replicated.

Proposed experiments

Restore acetyl-CoA in miR-140 knock-in chondrocytes and rescore the growth plate

exp_sedn_acetyl_coa_rescue

Supply acetate or citrate, or overexpress Acly, in Mir140 knock-in mice or their primary chondrocytes and measure histone acetylation, Fgfr3 expression, resting-zone width and resting chondrocyte proliferation against untreated mutants. A rescue would convert the acetyl-CoA account of this disease from a phenotypic parallel between three mouse lines into a demonstrated mechanism.

Show evidence (2 references)

PMID:36711926 SUPPORT Model Organism

"However, the mechanism by which Ac-CoA deficiency can lead to the Fgfr3 upregulation and these phenotypic changes is not clear at the moment."

The authors declining to claim the step this entry declines to curate. It is why the FGFR3 arm is a discussion rather than an edge.

PMID:36711926 SUPPORT Model Organism

"These data demonstrate the association between reduced glycolysis and an expansion of the resting zone and suggest that it is caused by acetyl-CoA deficiency, but not energy deficiency, possibly through epigenetic upregulation of FGFR3 signaling."

The strength of claim the paper itself makes, with its two hedges - "suggest" and "possibly" - which the curation follows.

Is there any treatment to curate for this disorder?

KNOWLEDGE GAP OPEN sedn_no_treatment

Attached to

treatments#

No, and this entry deliberately has no treatments block. No disease-modifying therapy exists, none has been proposed in the literature, and no clinical trial keyed to MIR140 or to this disorder was found. Nor has any intervention been tested in the mouse models: the knock-in line has been used for mechanism and never as a therapeutic testbed, which is a difference from the MIR96 entry, where preclinical gene editing and a repurposed drug are curated as rescue links on a mouse model. General management of a skeletal dysplasia - orthopaedic and spinal surveillance, pain and joint management, physiotherapy, airway assessment where there is stridor, genetic counselling - is what these patients will receive in practice, and none of it is reported for these three individuals. Importing it would attribute to them an experience recorded only of other people with other skeletal dysplasias, and in the exported graph a borrowed management statement is indistinguishable from an observed one. Closing this gap needs no new science, only a follow-up report on the patients already identified.

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Pathophysiology

15

MIR140 Seed-Region Point Mutation

A single-nucleotide substitution, NR_029681.1:n.24A>G (chr16:g.69967007A>G, hg19), at the first nucleotide of the seed of mature miR-140-5p. The seed is what selects a microRNA's target set, so a substitution there changes which transcripts miR-140-5p recognises. The same substitution is present in all three reported patients from two unrelated families, is absent from gnomAD, and the affected nucleotide is conserved from human to Australian ghostshark.

MIR140 hgnc:31527

Genetic context MIR140 hgnc:31527 allele_type: single-nucleotide substitution at the first seed nucleotide of the mature miR-140-5p strand variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: NEOMORPHIC

Carriers are heterozygous. The variant arose de novo in the probands of both families and was transmitted once, mother to son.

On the choice of NEOMORPHIC, and how it differs from the sibling miRNA entry. The other microRNA disease in this knowledge base, Autosomal_Dominant_Nonsyndromic_Hearing_Loss_50 (MIR96), deliberately leaves functional_impact_category absent, on the ground that a seed mutation is simultaneously hypomorphic for the wild-type target set and neomorphic for an acquired one and that no single-valued category says both. The biology is the same here. The reason the value is set anyway is that the mouse genetics assigns the disease-defining features to the acquired half in a way the MIR96 work does not. The miR-140-null mouse is not phenotypically silent - it is smaller with a shorter nose - but it does not have the delayed secondary ossification, the widened basal skull growth plate or the expanded resting zone that the knock-in mouse and the patients have, and the founding authors state in those words that the substitution is "neomorphic, and not just loss-of-function". NEOMORPHIC in Muller's sense names an allele with a new activity and does not deny that the old one is also impaired; the impaired half is curated as its own node, "Loss of Repression of Wild-Type miR-140-5p Targets", with its own evidence. What the single value cannot record is that the shared short stature and craniofacial features track the abandoned half while the epiphyseal features track the acquired one, and that is stated here rather than left to be inferred.

Downstream

Abundant Production of the Mutant miR-140-5p

Loss of Repression of Wild-Type miR-140-5p Targets

Repression of Novel Targets Acquired by the Mutant Seed

Show evidence (3 references)

PMID:30804514 SUPPORT Human Clinical

"Whole genome sequencing (WGS) identified the same heterozygous nucleotide substitution (chr16:g.69967007A>G (hg19), MIR140:NR_029681.1:n.24A>G) in P1 and P2"

The variant itself, in both coordinate systems, and the fact that it recurs.

PMID:30804514 SUPPORT Human Clinical

"This substitution is located at the first nucleotide of the seed sequence of the highly conserved microRNA (miRNA), miR-140-5p, encoded by MIR140"

Places the substitution in the seed, which is what makes the lesion a change of target specificity rather than a change of dose.

PMID:30804514 SUPPORT Human Clinical

"Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia."

The mechanism class the entry is built on, stated by the authors: a neomorphic seed mutation in a microRNA gene.

Abundant Production of the Mutant miR-140-5p

The mutant strand is made in quantity. Small RNA sequencing of knock-in mouse chondrocytes finds slightly more mutant miR-140-5p than wild-type miR-140-5p, with only minor shifts in Dicer processing and strand choice, so the substitution does not act by crippling biogenesis. Because MIR140 sits in a chondrocyte-specific super-enhancer, the mutant product is delivered at high level precisely in the cells the disease affects. This is the node that separates the lesion from the MIR96 Italian allele, which is a processing defect and reduces mature microRNA yield without changing what it targets.

MIR140 hgnc:31527

Downstream

Repression of Novel Targets Acquired by the Mutant Seed

Show evidence (2 references)

PMID:30804514 SUPPORT INDIRECT In Vitro

"Small RNA sequencing analysis in mouse chondrocytes revealed that the miR-140 A>G mutation yields slightly greater amounts of the mutant miR-140-5p (miR-140-5p-G) than wild-type miR-140-5p, while decreasing two miR-140-3p species (3p.1 and 3p.2)"

The quantitative measurement behind the node, including the incidental fall in the two 3p species. Indirect because it is primary mouse chondrocytes rather than human cartilage.

PMID:30804514 SUPPORT INDIRECT In Vitro

"These data indicate that the A>G mutation did not compromise miRNA processing and yielded abundant expression of miR-140-5p-G from primary miR-140 transcripts of which transcription is strongly activated by a super-enhancer in chondrocytes."

The authors' own reading: processing is intact and the super-enhancer supplies the mutant product at high level in chondrocytes.

Loss of Repression of Wild-Type miR-140-5p Targets

Transcripts carrying a wild-type miR-140-5p site are no longer repressed and rise. This half of the mechanism is shared with a plain deletion of the microRNA: conserved 8mer targets of wild-type miR-140-5p are de-repressed both in the knock-in and in the null. The reading is quantitative - silencing of this particular target set falls - which is why the modifier is DECREASED.

miRNA-mediated post-transcriptional gene silencing of the wild-type miR-140-5p target set GO:0035195 ↓ DECREASED

Animal models

miR-140-null mouse Mouse recapitulates A deletion reproduces the abandoned half of the mechanism exactly, since removing the microRNA is the cleanest possible way to de-repress its normal targets. It is the reference against which the knock-in transcriptome was read.

Downstream

Dysregulation of the Chondrocyte Maturation Programme

Show evidence (2 references)

PMID:30804514 SUPPORT INDIRECT In Vitro

"Both the miR-140 A>G mutation and miR-140 deletion caused derepression of conserved 8mer target genes for wild-type miR-140-5p and to a lesser extent for miR-140-3p species"

The de-repression itself, and the comparison that makes it the shared half of the mechanism: the deletion does the same thing.

PMID:30804514 SUPPORT INDIRECT In Vitro

"In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects."

The authors' summary of the two arms. It is the sentence that justifies splitting the target repertoire into two nodes instead of one dysregulation node.

Repression of Novel Targets Acquired by the Mutant Seed

The mutant seed is complementary to a different heptamer, so transcripts carrying that match - which wild-type miR-140-5p ignored - are repressed for the first time. The signature is specific to the substitution: widespread suppression of predicted mutant-seed targets is seen in knock-in chondrocytes and not in the null. The acquired set includes genes central to cartilage, among them Loxl3, Btg1 and Trps1, and Hif1a through a conserved match in its coding sequence.

TRPS1 repression by the mutant seed as the route to cone-shaped epiphyses

LOXL3 hgnc:13869 BTG1 hgnc:1130 TRPS1 hgnc:12340 HIF1A hgnc:4910

miRNA-mediated post-transcriptional gene silencing of transcripts complementary to the mutant seed GO:0035195

Animal models

Mir140 n.24A>G knock-in mouse Mouse recapitulates The chondrocyte transcriptome of this line is where the acquired target set was demonstrated, and where it was shown to be absent from the null.

Downstream

Suppression of YBX1-Dependent Transcript Stabilization

Repression of HIF1A and Blunted Chondrocyte Hypoxia Response

Dysregulation of the Chondrocyte Maturation Programme

Cone-Shaped Phalangeal Epiphyses A hypothesis-tagged edge, not an established one. It exists only under the trps1_cone_epiphysis_bridge hypothesis, which proposes that repression of the acquired target TRPS1 is what produces the cone-shaped epiphyses. Read the hypothesis before reading this edge; the intermediates are not known and the target has not been measured in this disease.

Show evidence (2 references)

PMID:30804514 SUPPORT INDIRECT In Vitro

"Importantly, the widespread suppression of predicted miR-140-5p-G targets is only observed in miR-140G/G and miR-140G/+ chondrocytes"

The result that isolates the acquired arm: only genotypes carrying the substitution show it, so a null allele cannot reproduce it.

PMID:30804514 SUPPORT INDIRECT In Vitro

"The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways"

Names the acquired targets and states why they matter here: they are cartilage genes, which is what makes an evolutionarily naive seed pathogenic in this tissue.

Suppression of YBX1-Dependent Transcript Stabilization

The explanation the founding study offers for why a seed with no evolutionary history with its targets nonetheless represses them hard. The hexamer complementary to the mutant seed, ACCACC, is one of the motifs bound by YBX1, an RNA-binding protein that stabilises transcripts, so the mutant microRNA in the Ago2 complex and YBX1 compete for the same 3-prime UTR sites. Ago2 and Ybx1 seCLIP in knock-in chondrocytes show both sides of that competition, acquired targets that also carry YBX1 binding are repressed more strongly than those that do not, and previously reported YBX1-stabilised transcripts fall preferentially in mutant rather than null chondrocytes.

chondrocyte CL:0000138

YBX1 hgnc:8014

Downstream

Dysregulation of the Chondrocyte Maturation Programme

Show evidence (3 references)

PMID:30804514 SUPPORT Computational

"Computational analysis suggested that the miR-140-5p-G seed in the Ago2 complex and the RBP, Ybx1 (also known as YB-1), potentially compete for the same RNA binding sites"

The hypothesis and its origin. Graded COMPUTATIONAL because this sentence reports a motif-overlap prediction; the experimental tests are quoted separately.

PMID:30804514 SUPPORT INDIRECT In Vitro

"Importantly, miR-140-5p-G Ago2 seCLIP target genes with Ybx1 binding in the 3′ UTR showed stronger repression in mutant chondrocytes than those without Ybx1 binding"

The measurement that converts the motif overlap into a functional claim: YBX1 occupancy predicts how hard the acquired target is repressed.

PMID:30804514 SUPPORT INDIRECT In Vitro

"These observations collectively suggest that the potent suppressive effect of miR-140-5p-G is partly attributable to the competition against Ybx1, especially in 3′ UTRs, and subsequent suppression of Ybx1 activity."

The authors' own weighting, and the reason this node is PROVISIONAL: they claim a partial attribution, not the whole effect.

Repression of HIF1A and Blunted Chondrocyte Hypoxia Response

The best-followed of the acquired targets. The coding region of Hif1a carries a conserved match to the mutant seed, Hif1a protein falls in knock-in chondrocytes, and gene set enrichment shows the hypoxia programme impaired in the knock-in but not in the null - so this is an acquired-target effect and not a consequence of losing the microRNA. The growth plate is avascular and hypoxic, which is why a transcription factor for hypoxic adaptation is load-bearing in this tissue.

chondrocyte CL:0000138

HIF1A hgnc:4910

cellular response to hypoxia GO:0071456 ↓ DECREASED

Downstream

Reduced Lysyl Oxidase Expression and Collagen Cross-Linking

Reduced Chondrocyte Glycolysis with Compensatory Mitochondrial Metabolism

Show evidence (3 references)

PMID:30804514 SUPPORT INDIRECT In Vitro

"Furthermore, gene set enrichment analysis (GSEA) revealed that the hypoxia pathway is impaired in miR-140G/G, but not in miR-140−/− chondrocytes"

The genotype contrast that assigns the blunted hypoxia response to the acquired arm rather than to loss of the microRNA.

PMID:30804514 SUPPORT INDIRECT In Vitro

"Hif1a protein expression was reduced in miR-140G/G chondrocytes"

The protein-level measurement behind the node.

PMID:36711926 SUPPORT INDIRECT In Vitro

"We found that the miR-140 mutant chondrocytes showed a significant reduction of Hif1a, the master transcription factor that regulates energy metabolism in response to hypoxia."

The same finding restated by the group that made it, and the starting point of the metabolic branch curated below.

Reduced Lysyl Oxidase Expression and Collagen Cross-Linking

Lysyl oxidases are HIF1A-regulated and are the enzymes that cross-link collagen. Their transcripts fall in knock-in chondrocytes and mass spectrometry of rib cartilage from the same mice shows the cross-links themselves reduced. LOXL3 is separately one of the acquired targets of the mutant seed, so this node is reached both directly and through HIF1A.

chondrocyte CL:0000138

LOXL3 hgnc:13869

collagen fibril organization GO:0030199 ↓ DECREASED

Downstream

Delayed Endochondral Ossification of Epiphyses and Tubular Bones

Show evidence (1 reference)

PMID:30804514 SUPPORT INDIRECT Model Organism

"mRNA expression of Hif1a and Hif1a-regulated molecules including lysyl oxidases, essential for collagen crosslinking, significantly decreased in miR-140G/G chondrocytes, with a concomitant decrease in collagen crosslinking in the rib cartilage"

Transcript and cross-link measurements in the same sentence, which is what makes this a structural consequence rather than an expression change alone.

Reduced Chondrocyte Glycolysis with Compensatory Mitochondrial Metabolism

HIF1A stimulates glycolysis and restrains mitochondrial metabolism, so its repression reverses both. In knock-in chondrocytes glycolytic genes fall while mitochondrial genes rise in a dose-dependent way, and Seahorse measurement of extracellular acidification and oxygen consumption confirms the reciprocal shift.

chondrocyte CL:0000138

Downstream

Reduced Acetyl-CoA Availability and Histone Acetylation

Show evidence (2 references)

PMID:36711926 SUPPORT INDIRECT In Vitro

"We found that the expression of genes whose products of which function is related to energy metabolism was significantly altered; those that regulate glycolysis was reduced, whereas those that regulate mitochondrial function and metabolism were reciprocally upregulated in a dose-dependent manner"

The transcriptomic form of the shift, in primary chondrocytes from the original knock-in line, with a gene-dose relationship.

PMID:36711926 SUPPORT INDIRECT In Vitro

"In this study, we show that the disease-causing GOF mutant miR-140 decreases glycolysis and increases OXPHOS in growth plate chondrocytes, that reduced glycolysis via Ldh ablation increases resting chondrocyte proliferation and reduces histone acetylation, and that Acly disruption causes..."

The paper's own summary, which also states plainly that the middle of the chain was tested in Ldh and Acly knockouts rather than in the miR-140 mutant.

Reduced Acetyl-CoA Availability and Histone Acetylation

Less glycolytic flux means less mitochondria-derived citrate and so less cytoplasmic acetyl-CoA, the acetyl donor for histone acetylation. Histone acetylation is reduced both in the miR-140 mutant and in Ldha-deficient chondrocytes. Deleting Acly, which converts citrate to acetyl-CoA, reproduces the growth plate phenotype without producing an energy deficit, which is the experiment that separates the acetyl-CoA explanation from a simple ATP shortage.

chondrocyte CL:0000138

Downstream

Resting-Zone Chondrocyte Expansion

Show evidence (2 references)

PMID:36711926 SUPPORT INDIRECT Model Organism

"We have also found that reduced glycolysis results in reduced histone acetylation in the miR-140 mutant as well as LDH-deficient chondrocytes likely due to the reduction in acetyl-CoA generated from mitochondria-derived citrate."

The measurement in the miR-140 mutant, together with the surrogate model that supports the same reading.

PMID:36711926 SUPPORT INDIRECT Model Organism

"Reduction in acetyl-CoA conversion from citrate by deleting Acly caused an expansion of the resting zone and a similar gross phenotype to LDH-deficient bones without inducing energy deficiency, suggesting that the reduced acetyl-CoA, but not the ATP synthesis deficit, is responsible for the..."

The control that makes acetyl-CoA rather than ATP the operative variable, and the source of the causal direction on the edge out of this node.

Resting-Zone Chondrocyte Expansion

The distinctive growth plate lesion of this disease. Resting-zone chondrocytes, the most immature population in the growth plate, proliferate more and accumulate, so the resting zone and the growth plate as a whole are expanded - in the proximal tibia and in the spheno-occipital synchondrosis of the basal skull. Proliferating columnar chondrocytes are not similarly affected, and the null mouse does not show the lesion at all.

chondrocyte CL:0000138

growth plate UBERON:0002516

Animal models

Mir140 n.24A>G knock-in mouse Mouse recapitulates The proximal tibial growth plate and the basal skull growth plate are both expanded, and the expansion is in the resting zone. This is the lesion the later metabolic work was built to explain.

Downstream

Delayed Endochondral Ossification of Epiphyses and Tubular Bones

Widened Cranial Base Growth Plate

Show evidence (4 references)

PMID:30804514 SUPPORT INDIRECT Model Organism

"The proximal tibial growth plate also showed an expansion of the resting zone in miR-140G/G and miR-140G/+ mice"

The lesion in the original knock-in line, present in heterozygotes as well as homozygotes.

PMID:30804514 SUPPORT INDIRECT Model Organism

"The basal skull growth plate was wider due to the increased length of all layers of chondrocytes in miR-140G/G and miR-140G/+ mice, whereas miR-140−/− mice showed no significant changes"

The same lesion at the cranial base, with the null comparison that assigns it to the substitution rather than to loss of the microRNA.

PMID:36711926 SUPPORT INDIRECT Model Organism

"EdU labeling revealed a significant increase in cell proliferation in resting zone chondrocytes but not in proliferating chondrocytes"

What the expansion consists of - a selective increase in resting-zone proliferation, in an enhanced-expression knock-in line.

+ 1 more reference

Dysregulation of the Chondrocyte Maturation Programme

The two target-repertoire changes and the YBX1 competition converge on a chondrocyte transcriptome that is shifted rather than destroyed. Col10a1, the marker of hypertrophic maturation, and other extracellular matrix transcripts fall in knock-in chondrocytes. Neither proliferation nor apoptosis in the tibial growth plate differs from wild type, so the lesion is a failure to mature rather than loss of cells.

chondrocyte CL:0000138 hypertrophic chondrocyte CL:0000743

COL10A1 hgnc:2185

chondrocyte differentiation GO:0002062 ↕ DYSREGULATED

Downstream

Delayed Endochondral Ossification of Epiphyses and Tubular Bones

Delayed Maturation of Laryngeal, Tracheal and Costal Cartilage

Show evidence (3 references)

PMID:30804514 SUPPORT INDIRECT In Vitro

"In addition, expression of several extracellular matrix genes including Col10a1 decreased in miR-140G/G and miR-140G/+ chondrocytes"

The transcriptional shift, in both mutant genotypes, including the hypertrophic maturation marker.

PMID:30804514 SUPPORT INDIRECT Model Organism

"The proliferation rate of tibial growth plate chondrocytes was not significantly different among miR-140G/G, miR-140G/+, and wild-type mice"

A negative result that constrains the mechanism: the growth plate abnormality is not a proliferation defect.

PMID:30804514 SUPPORT INDIRECT Model Organism

"We did not find an increased number of apoptotic cells in the growth plate of miR-140G/G mice"

The second negative: it is not cell death either.

Delayed Endochondral Ossification of Epiphyses and Tubular Bones

The tissue-level lesion the radiographs show. Secondary ossification of tubular and carpal bones is delayed and epiphyseal mineralization is severely reduced in the knock-in mouse, in heterozygotes as well as homozygotes, and the same abnormalities are consistent from postnatal day 7 to day 56. Vertebral bodies are mildly flattened. The authors state that the mouse findings correspond to the patients' delayed secondary ossification, mild platyspondyly, small epiphyses and scaphocephaly.

endochondral ossification GO:0001958 ↓ DECREASED

secondary ossification center UBERON:0010357 epiphysis UBERON:0001437

Animal models

Mir140 n.24A>G knock-in mouse Mouse recapitulates Heterozygous knock-in mice have delayed secondary ossification of tubular and carpal bones and severely reduced epiphyseal mineralization, which the authors map directly onto the patients' delayed secondary ossification and small epiphyses.

miR-140-null mouse Mouse fails to recapitulate The null mouse does not reproduce the disease's defining skeletal lesion. It does not have the delayed secondary ossification, and its growth plate runs the other way: endochondral bone development is mildly advanced, with accelerated hypertrophic differentiation. This negative is the load-bearing result of the entry - it is why the substitution is read as neomorphic rather than as a loss of function.

Downstream

Disproportionate Short-Limb Short Stature

Severe Brachydactyly

Cone-Shaped Phalangeal Epiphyses

Delayed Epiphyseal Ossification

Small Epiphyses

Small Hands

Short Feet

Platyspondyly

Premature Degeneration of Spine and Joints

Show evidence (3 references)

PMID:30804514 SUPPORT INDIRECT Model Organism

"only miR-140G/G and miR-140G/+ mice showed delayed secondary ossification of tubular and carpal bones"

The core skeletal lesion, and the word "only" - the null mice in the same experiment did not have it.

PMID:30804514 SUPPORT INDIRECT Model Organism

"Micro-CT analysis showed severely decreased epiphyseal mineralization in miR-140G/G mice"

The quantitative imaging measurement of the same lesion.

PMID:30804514 SUPPORT INDIRECT Model Organism

"These bone abnormalities of miR-140G/G and miR-140G/+ mice are consistent at all analyzed ages from P7 to P56 when compared to wild-type mice"

The mouse half of the correspondence: the same abnormalities at every age examined from postnatal day 7 to day 56. The human half of the same sentence is quoted on the phenotypes it names.

Widened Cranial Base Growth Plate

The cranial counterpart of the growth plate lesion. The spheno-occipital synchondrosis, a bidirectional growth plate in the basal skull, is widened in knock-in mice and not in null mice. Cranial base growth sets midfacial projection and skull shape, which is the route by which a chondrocyte disease produces midface hypoplasia, a small nose and scaphocephaly.

chondrocyte CL:0000138

growth plate UBERON:0002516

Downstream

Midface Hypoplasia

Short Nose

Scaphocephaly

Show evidence (2 references)

PMID:30804514 SUPPORT INDIRECT Model Organism

"The basal skull growth plate was wider due to the increased length of all layers of chondrocytes in miR-140G/G and miR-140G/+ mice, whereas miR-140−/− mice showed no significant changes"

The measurement, with the null comparison.

PMID:36711926 SUPPORT INDIRECT Model Organism

"In the spheno-occipital synchondrosis, a bidirectional growth plate in the basal skull, showed an expansion of the resting zone"

Identifies the structure by name and attributes the widening to the same resting-zone expansion seen in the tibia. Quoted from the Ldha knockout arm of the preprint, so it supports the anatomy and the lesion type rather than the miR-140 genotype specifically.

Delayed Maturation of Laryngeal, Tracheal and Costal Cartilage

Cartilage maturation is delayed outside the growth plate as well. Alizarin red staining shows delayed maturation of the larynx, trachea and anterior ribs in knock-in mice. In the two patients of Family 1 this corresponds to inspiratory stridor and recurrent respiratory infection, and in the proband to a narrow larynx attributed to floppy cartilage on fiberscopy.

larynx UBERON:0001737 trachea UBERON:0003126

Downstream

Laryngomalacia

Inspiratory Stridor

Recurrent Respiratory Infections

Show evidence (2 references)

PMID:30804514 SUPPORT INDIRECT Model Organism

"decreased expression of Col10a1, a maturation marker for hypertrophic chondrocytes (Extended Data Fig. 3b), and delayed cartilage maturation of the larynx, trachea, and anterior ribs"

Names the three extraskeletal cartilages involved, alongside the maturation marker that falls with them.

PMID:30804514 SUPPORT Human Clinical

"P1 had a narrow larynx likely due to floppy cartilage"

The human counterpart, and the clinicians' own attribution of the airway finding to cartilage rather than to a neuromuscular or infectious cause.

Premature Degeneration of Spine and Joints

The adult phase. The spondylar and epiphyseal abnormalities of childhood do not stabilise: they progress to premature spondylosis and degenerative joint disease. Reduced collagen cross-linking in cartilage is a plausible contributor, and independently miR-140-null mice develop age-related osteoarthritis-like change, but no joint tissue from a patient has been examined and the molecular bridge is not established.

Downstream

Premature Osteoarthritis

Show evidence (3 references)

PMID:30804514 SUPPORT Human Clinical

"The spondylar and epiphyseal abnormalities evolved into premature spondylosis and degenerative joint disease in adulthood, respectively."

The observed adult course in the reported patients.

PMID:20466812 SUPPORT INDIRECT Model Organism

"Interestingly, miR-140(-/-) mice showed age-related OA-like changes characterized by proteoglycan loss and fibrillation of articular cartilage."

Establishes that miR-140 has a joint-maintenance role independent of development. Indirect for this node because the genotype is a null, not the seed substitution, so it shows that the pathway matters for joints without showing that this allele acts through it.

PMID:41242538 NO_EVIDENCE Model Organism

"In contrast, its influence on post-traumatic OA is modest, with limited impact on cartilage degeneration but a role in modulating osteophyte formation."

The counterweight, and the reason this node is not built on the osteoarthritis literature. A newer null mouse subjected to destabilisation of the medial meniscus shows only a modest increase in cartilage damage, with no enrichment of predicted miR-140-5p targets among the upregulated genes. Graded NO_EVIDENCE for this node because it neither supports nor refutes a claim about the seed allele - it constrains how much the null mouse osteoarthritis result can be leaned on.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

15

Head and Neck 2

Midface Hypoplasia VERY_FREQUENT Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."

The clinical description of the entity, from the report that defined it.

Short Nose VERY_FREQUENT HP:0003196

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."

The clinical description of the entity, from the report that defined it.

Immune 1

Recurrent Respiratory Infections FREQUENT HP:0002205

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"P1 and P2 also suffered from frequent respiratory infections with prolonged cough and inspiratory stridor."

The infections and the individuals in whom they occurred.

PMID:30804514 SUPPORT Human Clinical

"All three affected individuals had normal intelligence, dentition, hearing, visual acuity, and basic blood tests."

The negative that argues against an immunological explanation, and separately records that the disorder is not syndromic beyond the skeleton and airway.

Limbs 3

Small Hands VERY_FREQUENT HP:0200055

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."

The clinical description of the entity, from the report that defined it.

Short Feet VERY_FREQUENT Short foot HP:0001773

The source says "small hands and feet". HP:0001773 Short foot is the closest available term; HPO has no "small foot" concept matching the hand term, so the binding trades exactness of wording for an existing term rather than manufacturing a narrower match.

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."

The clinical description of the entity, from the report that defined it.

Severe Brachydactyly VERY_FREQUENT HP:0001156

Severity: SEVERE

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"

The three radiological hallmarks, stated together, including the severity qualifier.

Musculoskeletal 3

Delayed Epiphyseal Ossification VERY_FREQUENT HP:0002663

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"

The three radiological hallmarks, stated together.

Platyspondyly VERY_FREQUENT HP:0000926

Severity: MILD

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"

The word platyspondyly applied to the patients, with the mild qualifier that the severity slot records.

Premature Osteoarthritis FREQUENT HP:0003088

FREQUENT rather than VERY_FREQUENT because this is an adult-onset feature and only one of the three reported patients was an adult at the time of the report; the youngest is a child. It is a statement about the disorder's course rather than a count of affected individuals.

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"The spondylar and epiphyseal abnormalities evolved into premature spondylosis and degenerative joint disease in adulthood, respectively."

The adult outcome of the two childhood radiographic abnormalities.

Growth 1

Disproportionate Short-Limb Short Stature VERY_FREQUENT HP:0008873

Frequency here and on the other core skeletal features is a description of a three-patient series, not a population estimate. The source states these as the clinical features of the disorder rather than giving a per-patient count, so VERY_FREQUENT is used in preference to OBLIGATE, which would assert complete penetrance from three observations.

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."

The clinical description of the entity, from the report that defined it.

Other 5

Cone-Shaped Phalangeal Epiphyses VERY_FREQUENT Cone-shaped epiphysis HP:0010579

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"

The three radiological hallmarks, stated together.

Small Epiphyses VERY_FREQUENT HP:0010585

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"

The patient feature list given when the authors compare their mice with the humans. The clause quoted is the human half of that comparison.

Scaphocephaly VERY_FREQUENT HP:0030799

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"

The patient feature list in the mouse-to-human comparison.

Laryngomalacia FREQUENT HP:0001601

FREQUENT rather than VERY_FREQUENT because the airway findings are reported for the two members of Family 1 and not for the third patient, and the fiberscopic diagnosis is documented for one individual only.

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"P1 had a narrow larynx likely due to floppy cartilage"

The finding and its attribution to cartilage.

PMID:30804514 SUPPORT Human Clinical

"Fiberscopy findings in P1, 44 years of age, consistent with laryngomalacia."

The endoscopic diagnosis in the term used by HPO, with the age at which it was made.

Inspiratory Stridor FREQUENT HP:0005348

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"P1 and P2 also suffered from frequent respiratory infections with prolonged cough and inspiratory stridor."

The airway symptoms and the two individuals in whom they were recorded.

🧬

Genetic Associations

1

MIR140

Gene: MIR140 hgnc:31527 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"Because the phenotype has not been reported previously and these patients were found to have the same variant in the MIR140 gene, we propose the eponym of spondyloepiphyseal dysplasia (SED) MIR140 type Nishimura."

The gene-disease relationship as established, and the origin of the disorder's name.

PMID:30804514 SUPPORT Human Clinical

"Screening P1, P2, and P3 for possible disease causing variants in 378 known skeletal dysplasia genes using WGS data, and screening P2 for gene dose abnormalities of the above mentioned skeletal dysplasia genes using custom-designed comparative genome hybridization analysis was all negative"

The exclusion work behind the gene assignment: 378 known skeletal dysplasia genes and a dosage screen, all negative, before MIR140 was implicated.

🔬

Diagnosis

1

MIR140 sequencing in an unexplained spondyloepiphyseal dysplasia with brachydactyly

The route to this diagnosis is radiographic recognition followed by sequencing that actually covers MIR140. The practical trap is structural: MIR140 is a short non-coding gene, so an exome pipeline built around coding exons will not find the variant. In both families exome sequencing was performed first and returned nothing in the protein-coding genes; whole genome sequencing, searching non-coding as well as coding genes, found the substitution. A panel of 378 known skeletal dysplasia genes and a dosage array were also negative. Once the entity was recognised in the second family, Sanger sequencing of MIR140 was sufficient.

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"No potential disease causing variants were found in the protein coding genes."

The exome result in both families, and the reason a coding-only analysis will miss this diagnosis.

PMID:30804514 SUPPORT Human Clinical

"Whole genome sequencing (WGS) identified the same heterozygous nucleotide substitution (chr16:g.69967007A>G (hg19), MIR140:NR_029681.1:n.24A>G) in P1 and P2"

The test that made the diagnosis, and the variant nomenclature to report.

📈

Progression

2

Childhood skeletal dysplasia

Disproportionate short stature, brachydactyly with cone-shaped epiphyses, delayed epiphyseal ossification and mild spondylar dysplasia are the childhood picture. In Family 1 the airway symptoms - prolonged cough and inspiratory stridor - are also present in this phase. No age at onset, growth velocity or bone-age series is quotable: auxology data are in a supplementary table that the cached record does not carry.

Show evidence (1 reference)

PMID:30804514 SUPPORT Human Clinical

"The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"

The radiographic features that define the childhood phase.

Adult degenerative phase

The skeletal abnormalities do not remain static after growth ends. Spondylar dysplasia progresses to premature spondylosis and the epiphyseal abnormalities to degenerative joint disease. Bone density was normal for age in the proband at 43, so this is a structural and degenerative course rather than a bone-mass disorder. Survival to at least the mid-forties is documented, and there is no report of a lethal outcome.

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"The spondylar and epiphyseal abnormalities evolved into premature spondylosis and degenerative joint disease in adulthood, respectively."

The adult course, stated for the reported patients.

PMID:30804514 SUPPORT Human Clinical

"She had normal bone density for the age, which suggests that the heterozygous MIR140 mutation in humans does not lead to bone mass abnormalities."

The one quantitative adult measurement published, and the negative it establishes: this is not a bone-fragility disorder.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No prevalence estimate exists. Three affected individuals in two unrelated families have been reported, in a single 2019 paper, and no further patient has appeared in the literature since. The families were ascertained through a project specifically directed at ultra-rare congenital skeletal disorders, which is a selected denominator rather than a population one. prevalence_class is the qualitative ULTRA_RARE tier and no rate_per_100000 is given, because none has been reported and a numeric band beside this note would be an invention.

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"A novel skeletal dysplasia was identified in two unrelated families in a project for molecular diagnosis of ultra-rare congenital skeletal disorders"

The number of families and the ascertainment route that found them.

PMID:36711926 SUPPORT Other

"We previously reported that a single nucleotide substitution of the MIR140 in humans caused ultra-rare skeletal dysplasia, spondyloepiphyseal dysplasia, Nishimura type"

The same group calling the disorder ultra-rare four years later, which is the closest thing to a rarity statement that exists. Graded OTHER because it is a preprint's introduction restating its own earlier human genetics rather than reporting patients.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Spondyloepiphyseal Dysplasia, Nishimura Type:

Acrodysostosis

Overlapping Features The differential the authors single out. Both disorders combine midface hypoplasia with brachydactyly and cone-shaped epiphyses, so the hands and face look similar. Two things separate them. Epiphyseal maturation is delayed in SED Nishimura type and advanced, particularly in the carpus, in acrodysostosis - the ossification clock runs the opposite way. And epiphyseal dysplasia, which is a hallmark here, is not a feature of acrodysostosis. The reported patients also had none of the endocrine abnormalities of acrodysostosis and no PDE4D or PRKAR1A variant.

Distinguishing Features

Delayed rather than advanced epiphyseal and carpal ossification
Epiphyseal dysplasia, which acrodysostosis does not have
No hypocalcaemia, hyperphosphataemia, raised PTH or TSH, or low IGF-1
No PDE4D or PRKAR1A variant

Show evidence (2 references)

PMID:30804514 SUPPORT Human Clinical

"The present disorder should be differentiated from acrodysostosis."

The authors naming the differential.

PMID:30804514 SUPPORT Human Clinical

"However, epiphyseal maturation is delayed in SED MIR140 type Nishimura, whereas epiphyseal ossification, particularly carpal ossification, is advanced in acrodysostosis."

The single most useful discriminator, and the direction it runs in.

📊

Related Datasets

2

miR-140 mutation and skeletal dysplasia geo:GSE98309

mouse BULK RNA SEQ

PMID:30804514

The transcriptomic and seCLIP data behind the founding study: primary rib chondrocytes from wild-type, knock-in and null mice. It is the dataset in which both arms of the mechanism are visible in one experiment. No evidence block, because an evidence item needs an exact quote supporting a specific claim and this record asserts only that the dataset exists and what it contains.

Regulatory role of energy metabolism in skeletal development geo:GSE192971

mouse BULK RNA SEQ

PMID:36711926

RNA-seq from Ldha and Acly conditional-knockout chondrocytes, the surrogate models used to test the metabolic branch. Relevant to this disease as the evidence base for the acetyl-CoA account rather than as a measurement of the miR-140 genotype.

🐁

Animal Models

2

Mir140 n.24A>G knock-in mouse

The model that carries the argument. CRISPR-Cas9 was used to introduce the patients' exact substitution into the mouse genome, and two independent founder lines gave the same phenotype. Heterozygotes, the genotype a patient has, show delayed secondary ossification, a widened basal skull growth plate, an expanded resting zone and mildly flattened vertebral bodies; homozygotes are more severely affected. The whole force of the model is the side-by-side comparison with miR-140-null mice, which do not have these features.

Species

Mouse

Genotype

Mir140 A>G knock-in (the human n.24A>G substitution), heterozygous and homozygous

Background

C57BL/6, two independent CRISPR-Cas9 founder lines

Genes

MIR140 hgnc:31527

Publication

PMID:30804514

Pathograph links

Repression of Novel Targets Acquired by the Mutant Seed recapitulates fidelity: high The chondrocyte transcriptome of this line is where the acquired target set was demonstrated, and where it was shown to be absent from the null.

Limitations: The acquired target set is defined in mouse chondrocytes and predicted by TargetScan; no human chondrocyte or patient cartilage has been profiled, so the specific transcripts repressed in a patient are inferred from orthology rather than measured. Repression of the acquired set was strongest for 8mer sites, so the reported effect is weighted towards the best-predicted subset.

Readouts

Expression of predicted mutant-seed target genes

Direction: DECREASED

Interpretation: Transcripts carrying a match to the mutant seed fall, and do so only in genotypes carrying the substitution.

Show evidence (1 reference)

PMID:30804514 SUPPORT In Vitro

"Importantly, the widespread suppression of predicted miR-140-5p-G targets is only observed in miR-140G/G and miR-140G/+ chondrocytes"

The measurement and the genotype restriction that makes it informative.

Show evidence (1 reference)

PMID:30804514 SUPPORT INDIRECT In Vitro

"In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects."

Establishes that this model is the system in which both arms of the mechanism were shown, which is what makes it informative for this node.

Delayed Endochondral Ossification of Epiphyses and Tubular Bones recapitulates fidelity: high Heterozygous knock-in mice have delayed secondary ossification of tubular and carpal bones and severely reduced epiphyseal mineralization, which the authors map directly onto the patients' delayed secondary ossification and small epiphyses.

Limitations: The correspondence between mouse and human is asserted by inspection of radiographs and histology rather than by a quantified morphometric comparison. Homozygous mice, in which the lesion is most severe, have no human counterpart - no homozygous patient has been reported. The mouse work was done on a single background, C57BL/6, and the timing of the mouse lesion is postnatal weeks against a human course measured in years.

Readouts

Secondary ossification of tubular and carpal bones

Direction: DECREASED

Interpretation: Ossification centres appear late, in heterozygotes as well as homozygotes, and not in null mice.

Show evidence (1 reference)

PMID:30804514 SUPPORT Model Organism

"only miR-140G/G and miR-140G/+ mice showed delayed secondary ossification of tubular and carpal bones"

The readout and the genotypes in which it is seen.

Epiphyseal mineralization by micro-computed tomography

Direction: DECREASED

Interpretation: Mineral content of the epiphysis is severely reduced in homozygotes.

Show evidence (1 reference)

PMID:30804514 SUPPORT Model Organism

"Micro-CT analysis showed severely decreased epiphyseal mineralization in miR-140G/G mice"

The quantitative imaging readout.

Show evidence (2 references)

PMID:30804514 SUPPORT Model Organism

"These bone abnormalities of miR-140G/G and miR-140G/+ mice are consistent at all analyzed ages from P7 to P56 when compared to wild-type mice"

The mouse side of the model-to-patient correspondence: the lesion is stable across every age examined rather than a transient developmental lag.

+ 1 more reference

Resting-Zone Chondrocyte Expansion recapitulates fidelity: moderate The proximal tibial growth plate and the basal skull growth plate are both expanded, and the expansion is in the resting zone. This is the lesion the later metabolic work was built to explain.

Limitations: Fidelity is MODERATE rather than HIGH because no human growth plate has ever been examined in this disease: the resting-zone lesion is a mouse finding whose human counterpart is inferred from the radiographic delay in ossification. The follow-up work also had to build an enhanced-expression line, with additional nucleotide changes that no patient carries, to make the phenotype robust in heterozygotes.

Readouts

Resting zone width of the proximal tibial growth plate

Direction: INCREASED

Interpretation: The resting zone is expanded in heterozygotes and homozygotes.

Show evidence (1 reference)

PMID:30804514 SUPPORT Model Organism

"The proximal tibial growth plate also showed an expansion of the resting zone in miR-140G/G and miR-140G/+ mice"

The readout and its direction.

Show evidence (1 reference)

PMID:36711926 SUPPORT Model Organism

"In the mouse model carrying the identical substitution as in patients, the resting zone of the growth plate was expanded, causing a delay in ossification and development of the epiphysis."

The later paper stating what this model established and why the resting-zone lesion is taken to explain the ossification delay.

miR-140-null mouse

Not a model of this disease but the control that defines it. Deleting the microRNA gives dwarfism and craniofacial deformity with mildly accelerated hypertrophic differentiation - a phenotype that overlaps the knock-in in stature and face but is opposite in the growth plate, where maturation is advanced rather than delayed. Null mice also develop age-related osteoarthritis-like change. Heterozygous nulls are normal.

Species

Mouse

Genotype

Mir140 targeted deletion, heterozygous and homozygous

Genes

MIR140 hgnc:31527

Publication

PMID:21576357

Pathograph links

Loss of Repression of Wild-Type miR-140-5p Targets recapitulates fidelity: high A deletion reproduces the abandoned half of the mechanism exactly, since removing the microRNA is the cleanest possible way to de-repress its normal targets. It is the reference against which the knock-in transcriptome was read.

Limitations: It reproduces only that half. A null allele cannot acquire targets, so nothing measured in this line speaks to the neomorphic arm, and features shared between null and knock-in cannot be attributed to either arm on the strength of this model alone.

Readouts

Expression of conserved wild-type miR-140-5p 8mer target genes

Direction: INCREASED

Interpretation: Normal targets rise in the deletion just as they do in the knock-in, which is what makes this arm the shared one.

Show evidence (1 reference)

PMID:30804514 SUPPORT In Vitro

"Both the miR-140 A>G mutation and miR-140 deletion caused derepression of conserved 8mer target genes for wild-type miR-140-5p and to a lesser extent for miR-140-3p species"

The direct comparison of the two genotypes on the same target set.

Show evidence (1 reference)

PMID:21576357 SUPPORT Model Organism

"In this paper, we show that loss of Mir140 in mice causes growth defects of endochondral bones, resulting in dwarfism and craniofacial deformities."

Establishes what losing the microRNA does on its own, which is the baseline the knock-in is compared against.

Delayed Endochondral Ossification of Epiphyses and Tubular Bones fails to recapitulate fidelity: low The null mouse does not reproduce the disease's defining skeletal lesion. It does not have the delayed secondary ossification, and its growth plate runs the other way: endochondral bone development is mildly advanced, with accelerated hypertrophic differentiation. This negative is the load-bearing result of the entry - it is why the substitution is read as neomorphic rather than as a loss of function.

Limitations: The failure is specific and not total: the null does reproduce the short stature and craniofacial abnormality, so it is informative for those features and for the abandoned target set. The comparison also has a confound worth stating - the null was made by targeted deletion in an earlier study and the knock-in by CRISPR-Cas9 in this one, so the two lines differ in provenance as well as in allele, and the phenotypes were scored across studies as well as within one.

Readouts

Timing of hypertrophic chondrocyte differentiation

Direction: INCREASED

Interpretation: Terminal differentiation is mildly advanced in the null, the opposite direction to the delay seen in the knock-in and in patients.

Show evidence (1 reference)

PMID:21576357 SUPPORT Model Organism

"Endochondral bone development is mildly advanced due to accelerated hypertrophic differentiation of chondrocytes in Mir140-null mice."

The direction of the null's growth plate phenotype, in the null paper's own words.

Show evidence (1 reference)

PMID:30804514 SUPPORT Model Organism

"Taken together, these differences in phenotype between miR-140G/G and miR-140−/− mice, and delayed epiphyseal maturation in humans, indicate that this single-base substitution causes a neomorphic, and not just loss-of-function, effect."

The inference the failure supports, stated by the authors: a null and this allele are not the same lesion.

{ }

Source YAML

click to show

name: Spondyloepiphyseal Dysplasia, Nishimura Type
category: Mendelian
creation_date: "2026-09-03T00:00:00Z"
synonyms:
- SEDN
- SED MIR140 type Nishimura
- spondyloepiphyseal dysplasia, MIR140 type
- MIR140-related skeletal dysplasia
description: >-
  Spondyloepiphyseal dysplasia, Nishimura type is an autosomal dominant skeletal dysplasia
  caused by a single heterozygous nucleotide substitution in MIR140, the gene encoding the
  chondrocyte-specific microRNA miR-140. It is the second miRNA-caused disease in this
  knowledge base, after DFNA50 (MIR96), and the first in which a mutant microRNA was shown
  to acquire a new function rather than merely lose its old one.

  MIR140 does not encode a protein. Its mature product miR-140-5p is expressed almost
  exclusively in chondrocytes and is transcribed from a chondrocyte-specific
  super-enhancer, so the gene is both cartilage-restricted and highly expressed there. The
  disease allele, NR_029681.1:n.24A>G, changes one nucleotide at the start of the miR-140-5p
  seed - the six-nucleotide stretch that selects which transcripts a microRNA silences. All
  three reported patients, in two unrelated families, carry that same substitution.

  What the seed change does is the point of the entry. It abandons the transcripts miR-140-5p
  normally represses, which rise; and it acquires transcripts complementary to the new seed,
  which are repressed for the first time. Both signatures are present in the same knock-in
  mouse chondrocyte transcriptome, and the paper's own summary is that the mutation "produces
  both loss-of-function and gain-of-function effects". Two independent results show that the
  acquired half is not incidental. A knock-in mouse carrying the human substitution has
  delayed secondary ossification, a widened basal skull growth plate and an expanded resting
  zone, none of which the miR-140-null mouse has; and heterozygous MIR140 deletions in humans
  are not associated with skeletal disease, so halving the wild-type dose is not what causes
  this disorder.

  The acquired targets are unusually potently repressed for a seed that has no evolutionary
  history with them, and the founding study offers a mechanism for that too: the new seed
  match, ACCACC, overlaps the binding motif of YBX1, an RNA-binding protein that stabilises
  transcripts. The mutant microRNA and YBX1 compete for the same 3-prime UTR sites, so
  binding by one displaces the stabilising effect of the other.

  Downstream, one acquired target has been followed further than the rest. HIF1A carries a
  conserved match to the mutant seed in its coding sequence; HIF1A protein falls, the hypoxia
  programme is blunted, lysyl oxidases fall and collagen cross-linking in cartilage decreases.
  A later preprint from the same group traces a second arm from the same node: glycolysis
  falls with a compensatory rise in mitochondrial metabolism, cytoplasmic acetyl-CoA and
  histone acetylation fall, and resting-zone chondrocytes proliferate and accumulate. That
  arm is curated as provisional, because its middle steps were established in Ldha and Acly
  conditional knockouts rather than in the miR-140 mutant itself.

  What reaches the clinic is disproportionate short-limb short stature with small hands and
  feet, severe brachydactyly with cone-shaped phalangeal epiphyses, delayed epiphyseal
  ossification of hip and knee, mild spondylar dysplasia and midface hypoplasia, evolving in
  adulthood into premature spondylosis and degenerative joint disease. Intelligence, hearing,
  vision and dentition are normal. There is no disease-modifying treatment and none has been
  proposed.
disease_term:
  preferred_term: spondyloepiphyseal dysplasia, Nishimura type
  term:
    id: MONDO:0032835
    label: spondyloepiphyseal dysplasia, nishimura type
parents:
- Spondyloepiphyseal Dysplasia
references:
- reference: PMID:30804514
  title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
- reference: PMID:36711926
  title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
- reference: PMID:21576357
  title: "Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling."
- reference: PMID:20466812
  title: "MicroRNA-140 plays dual roles in both cartilage development and homeostasis."
- reference: PMID:32745689
  title: "MicroRNAs in cartilage development and dysplasia."
- reference: PMID:41242538
  title: "Transcriptomic profiling confirms microRNA-140 is more functional in joint development than in disease."
- reference: PMID:28426188
  title: "Trichorhinophalangeal Syndrome."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    Three affected individuals in two unrelated families all carry the same heterozygous
    MIR140 substitution. It arose de novo in the two probands and was transmitted from an
    affected mother to her affected son. Dominance here is not haploinsufficiency: a
    heterozygous MIR140 deletion has not been associated with skeletal disease in humans and
    heterozygous miR-140 knockout mice are normal, so it is the presence of the mutant
    microRNA product, not the absence of half the wild-type dose, that produces the
    phenotype.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The same single nucleotide substitution occurred de novo in P1 and P3, and co-segregated with the skeletal dysplasia phenotype in Family 1"
    explanation: >-
      Both halves of the dominant argument in one sentence: two independent de novo events on
      the same nucleotide, and vertical segregation in the family that has two affected
      members.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This result suggests that haploinsufficiency of MIR140 does not lead to skeletal abnormalities in humans, consistent with the normal phenotype previously reported in heterozygous miR-140 knockout mice6, supporting the hypothesis that the heterozygous nucleotide substitution (chr16:g.69967007A>G (hg19), MIR140:NR_029681.1:n.24A>G) is a neomorphic mutation."
    explanation: >-
      The CNV-database search that rules out simple haploinsufficiency as the basis of the
      dominance, and the mouse result that agrees with it.
mechanistic_hypotheses:
- hypothesis_group_id: trps1_cone_epiphysis_bridge
  hypothesis_label: TRPS1 repression by the mutant seed as the route to cone-shaped epiphyses
  status: EMERGING
  description: >-
    A candidate bridge between one named acquired target and one specific patient feature.
    TRPS1 is among the genes the mutant miR-140-5p seed acquires as targets, and heterozygous
    TRPS1 loss of function causes trichorhinophalangeal syndrome, whose diagnostic radiographic
    finding is cone-shaped epiphyses - which is also one of the radiological hallmarks of this
    disorder. If the mutant microRNA represses TRPS1 in patient chondrocytes, that would be a
    single-target explanation for a phenotype that otherwise has to be attributed to a diffuse
    transcriptional shift.

    It is recorded as EMERGING rather than curated as an established edge because the founding
    paper names Trps1 in a list of acquired targets and does not attribute any patient feature
    to it. Nobody has measured TRPS1 in a miR-140 mutant chondrocyte, in a patient, or in a
    reporter assay against the TRPS1 3-prime UTR, and no epistasis experiment has been done.
    The two disorders also differ in almost everything else: trichorhinophalangeal syndrome has
    sparse hair, dystrophic nails and a distinctive nose, none of which is reported here, so if
    the bridge holds it is partial rather than a shared mechanism.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways"
    explanation: >-
      The half of the hypothesis that is established: Trps1 is among the transcripts the mutant
      seed acquires. The paper goes no further than naming it.
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "The clinical diagnosis of TRPS can be established in a proband with characteristic facial features, ectodermal and joint manifestations, and skeletal findings of cone-shaped epiphyses."
    explanation: >-
      The other half: cone-shaped epiphyses are the radiographic hallmark of the TRPS1 disease,
      which is what makes the acquired target interesting. Graded OTHER because a GeneReviews
      chapter is an expert synthesis rather than a study reporting its own data, and INDIRECT
      because it is about a different disorder.
pathophysiology:
- name: MIR140 Seed-Region Point Mutation
  biological_scale: MOLECULAR
  description: >-
    A single-nucleotide substitution, NR_029681.1:n.24A>G (chr16:g.69967007A>G, hg19), at the
    first nucleotide of the seed of mature miR-140-5p. The seed is what selects a microRNA's
    target set, so a substitution there changes which transcripts miR-140-5p recognises. The
    same substitution is present in all three reported patients from two unrelated families,
    is absent from gnomAD, and the affected nucleotide is conserved from human to Australian
    ghostshark.
  genes:
  - preferred_term: MIR140
    term:
      id: hgnc:31527
      label: MIR140
  genetic_context:
    genes:
    - preferred_term: MIR140
      term:
        id: hgnc:31527
        label: MIR140
    allele_type: single-nucleotide substitution at the first seed nucleotide of the mature miR-140-5p strand
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: NEOMORPHIC
    description: >-
      Carriers are heterozygous. The variant arose de novo in the probands of both families
      and was transmitted once, mother to son.
    notes: >-
      On the choice of NEOMORPHIC, and how it differs from the sibling miRNA entry. The other
      microRNA disease in this knowledge base, Autosomal_Dominant_Nonsyndromic_Hearing_Loss_50
      (MIR96), deliberately leaves functional_impact_category absent, on the ground that a
      seed mutation is simultaneously hypomorphic for the wild-type target set and neomorphic
      for an acquired one and that no single-valued category says both. The biology is the
      same here. The reason the value is set anyway is that the mouse genetics assigns the
      disease-defining features to the acquired half in a way the MIR96 work does not. The
      miR-140-null mouse is not phenotypically silent - it is smaller with a shorter nose -
      but it does not have the delayed secondary ossification, the widened basal skull growth
      plate or the expanded resting zone that the knock-in mouse and the patients have, and
      the founding authors state in those words that the substitution is "neomorphic, and not
      just loss-of-function". NEOMORPHIC in Muller's sense names an allele with a new
      activity and does not deny that the old one is also impaired; the impaired half is
      curated as its own node, "Loss of Repression of Wild-Type miR-140-5p Targets", with its
      own evidence. What the single value cannot record is that the shared short stature and
      craniofacial features track the abandoned half while the epiphyseal features track the
      acquired one, and that is stated here rather than left to be inferred.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole genome sequencing (WGS) identified the same heterozygous nucleotide substitution (chr16:g.69967007A>G (hg19), MIR140:NR_029681.1:n.24A>G) in P1 and P2"
    explanation: The variant itself, in both coordinate systems, and the fact that it recurs.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This substitution is located at the first nucleotide of the seed sequence of the highly conserved microRNA (miRNA), miR-140-5p, encoded by MIR140"
    explanation: >-
      Places the substitution in the seed, which is what makes the lesion a change of target
      specificity rather than a change of dose.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia."
    explanation: >-
      The mechanism class the entry is built on, stated by the authors: a neomorphic seed
      mutation in a microRNA gene.
  downstream:
  - target: Abundant Production of the Mutant miR-140-5p
  - target: Loss of Repression of Wild-Type miR-140-5p Targets
  - target: Repression of Novel Targets Acquired by the Mutant Seed
- name: Abundant Production of the Mutant miR-140-5p
  biological_scale: MOLECULAR
  description: >-
    The mutant strand is made in quantity. Small RNA sequencing of knock-in mouse chondrocytes
    finds slightly more mutant miR-140-5p than wild-type miR-140-5p, with only minor shifts in
    Dicer processing and strand choice, so the substitution does not act by crippling
    biogenesis. Because MIR140 sits in a chondrocyte-specific super-enhancer, the mutant
    product is delivered at high level precisely in the cells the disease affects. This is the
    node that separates the lesion from the MIR96 Italian allele, which is a processing defect
    and reduces mature microRNA yield without changing what it targets.
  genes:
  - preferred_term: MIR140
    term:
      id: hgnc:31527
      label: MIR140
  notes: >-
    No biological_processes descriptor is attached. The claim this node makes is that microRNA
    processing is unaffected, and ModifierEnum has no value for "unchanged" - INCREASED,
    DECREASED, ABNORMAL and DYSREGULATED would each assert a change that the cited measurement
    specifically did not find. The negative is the point, so it is carried by the description
    and the evidence rather than by a modifier.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Small RNA sequencing analysis in mouse chondrocytes revealed that the miR-140 A>G mutation yields slightly greater amounts of the mutant miR-140-5p (miR-140-5p-G) than wild-type miR-140-5p, while decreasing two miR-140-3p species (3p.1 and 3p.2)"
    explanation: >-
      The quantitative measurement behind the node, including the incidental fall in the two
      3p species. Indirect because it is primary mouse chondrocytes rather than human
      cartilage.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These data indicate that the A>G mutation did not compromise miRNA processing and yielded abundant expression of miR-140-5p-G from primary miR-140 transcripts of which transcription is strongly activated by a super-enhancer in chondrocytes."
    explanation: >-
      The authors' own reading: processing is intact and the super-enhancer supplies the
      mutant product at high level in chondrocytes.
  downstream:
  - target: Repression of Novel Targets Acquired by the Mutant Seed
- name: Loss of Repression of Wild-Type miR-140-5p Targets
  biological_scale: MOLECULAR
  description: >-
    Transcripts carrying a wild-type miR-140-5p site are no longer repressed and rise. This
    half of the mechanism is shared with a plain deletion of the microRNA: conserved 8mer
    targets of wild-type miR-140-5p are de-repressed both in the knock-in and in the null. The
    reading is quantitative - silencing of this particular target set falls - which is why the
    modifier is DECREASED.
  biological_processes:
  - preferred_term: miRNA-mediated post-transcriptional gene silencing of the wild-type miR-140-5p target set
    modifier: DECREASED
    term:
      id: GO:0035195
      label: miRNA-mediated post-transcriptional gene silencing
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Both the miR-140 A>G mutation and miR-140 deletion caused derepression of conserved 8mer target genes for wild-type miR-140-5p and to a lesser extent for miR-140-3p species"
    explanation: >-
      The de-repression itself, and the comparison that makes it the shared half of the
      mechanism: the deletion does the same thing.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects."
    explanation: >-
      The authors' summary of the two arms. It is the sentence that justifies splitting the
      target repertoire into two nodes instead of one dysregulation node.
  downstream:
  - target: Dysregulation of the Chondrocyte Maturation Programme
- name: Repression of Novel Targets Acquired by the Mutant Seed
  biological_scale: MOLECULAR
  description: >-
    The mutant seed is complementary to a different heptamer, so transcripts carrying that
    match - which wild-type miR-140-5p ignored - are repressed for the first time. The
    signature is specific to the substitution: widespread suppression of predicted mutant-seed
    targets is seen in knock-in chondrocytes and not in the null. The acquired set includes
    genes central to cartilage, among them Loxl3, Btg1 and Trps1, and Hif1a through a
    conserved match in its coding sequence.
  biological_processes:
  - preferred_term: miRNA-mediated post-transcriptional gene silencing of transcripts complementary to the mutant seed
    term:
      id: GO:0035195
      label: miRNA-mediated post-transcriptional gene silencing
  genes:
  - preferred_term: LOXL3
    term:
      id: hgnc:13869
      label: LOXL3
  - preferred_term: BTG1
    term:
      id: hgnc:1130
      label: BTG1
  - preferred_term: TRPS1
    term:
      id: hgnc:12340
      label: TRPS1
  - preferred_term: HIF1A
    term:
      id: hgnc:4910
      label: HIF1A
  notes: >-
    modifier is deliberately left absent on this descriptor, for the same reason it is left
    absent on the corresponding node of the MIR96 entry. What changed is the specificity of
    the silencing, not its level. INCREASED and DECREASED are the PATO-bound quantitative pair
    and would assert that an existing activity moved, which is not the claim - these
    transcripts had no miR-140-mediated silencing to increase. GAIN_OF_FUNCTION in ModifierEnum
    describes a process driven outside its normal regulatory constraints, which is activation
    of the same process rather than its redirection onto a different substrate set.
    DYSREGULATED still reads as a statement about level. The genes listed are the acquired
    targets named in the source; they are bound to human HGNC identifiers, but the
    measurements are in mouse chondrocytes.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Importantly, the widespread suppression of predicted miR-140-5p-G targets is only observed in miR-140G/G and miR-140G/+ chondrocytes"
    explanation: >-
      The result that isolates the acquired arm: only genotypes carrying the substitution show
      it, so a null allele cannot reproduce it.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways"
    explanation: >-
      Names the acquired targets and states why they matter here: they are cartilage genes,
      which is what makes an evolutionarily naive seed pathogenic in this tissue.
  downstream:
  - target: Suppression of YBX1-Dependent Transcript Stabilization
  - target: Repression of HIF1A and Blunted Chondrocyte Hypoxia Response
  - target: Dysregulation of the Chondrocyte Maturation Programme
  - target: Cone-Shaped Phalangeal Epiphyses
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trps1_cone_epiphysis_bridge
    description: >-
      A hypothesis-tagged edge, not an established one. It exists only under the
      trps1_cone_epiphysis_bridge hypothesis, which proposes that repression of the acquired
      target TRPS1 is what produces the cone-shaped epiphyses. Read the hypothesis before
      reading this edge; the intermediates are not known and the target has not been measured
      in this disease.
- name: Suppression of YBX1-Dependent Transcript Stabilization
  biological_scale: MOLECULAR
  description: >-
    The explanation the founding study offers for why a seed with no evolutionary history with
    its targets nonetheless represses them hard. The hexamer complementary to the mutant seed,
    ACCACC, is one of the motifs bound by YBX1, an RNA-binding protein that stabilises
    transcripts, so the mutant microRNA in the Ago2 complex and YBX1 compete for the same
    3-prime UTR sites. Ago2 and Ybx1 seCLIP in knock-in chondrocytes show both sides of that
    competition, acquired targets that also carry YBX1 binding are repressed more strongly
    than those that do not, and previously reported YBX1-stabilised transcripts fall
    preferentially in mutant rather than null chondrocytes.
  genes:
  - preferred_term: YBX1
    term:
      id: hgnc:8014
      label: YBX1
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  mechanism_confidence: PROVISIONAL
  notes: >-
    Confidence is PROVISIONAL rather than ESTABLISHED because the competition is inferred from
    motif overlap plus crosslinking and reporter experiments in mouse chondrocytes and HEK293T
    cells, and the authors themselves phrase the conclusion as a partial attribution. No
    experiment has removed YBX1 from a knock-in animal, and nothing has been measured in human
    cartilage.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Computational analysis suggested that the miR-140-5p-G seed in the Ago2 complex and the RBP, Ybx1 (also known as YB-1), potentially compete for the same RNA binding sites"
    explanation: >-
      The hypothesis and its origin. Graded COMPUTATIONAL because this sentence reports a
      motif-overlap prediction; the experimental tests are quoted separately.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Importantly, miR-140-5p-G Ago2 seCLIP target genes with Ybx1 binding in the 3′ UTR showed stronger repression in mutant chondrocytes than those without Ybx1 binding"
    explanation: >-
      The measurement that converts the motif overlap into a functional claim: YBX1 occupancy
      predicts how hard the acquired target is repressed.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These observations collectively suggest that the potent suppressive effect of miR-140-5p-G is partly attributable to the competition against Ybx1, especially in 3′ UTRs, and subsequent suppression of Ybx1 activity."
    explanation: >-
      The authors' own weighting, and the reason this node is PROVISIONAL: they claim a
      partial attribution, not the whole effect.
  downstream:
  - target: Dysregulation of the Chondrocyte Maturation Programme
- name: Repression of HIF1A and Blunted Chondrocyte Hypoxia Response
  biological_scale: MOLECULAR
  description: >-
    The best-followed of the acquired targets. The coding region of Hif1a carries a conserved
    match to the mutant seed, Hif1a protein falls in knock-in chondrocytes, and gene set
    enrichment shows the hypoxia programme impaired in the knock-in but not in the null - so
    this is an acquired-target effect and not a consequence of losing the microRNA. The growth
    plate is avascular and hypoxic, which is why a transcription factor for hypoxic adaptation
    is load-bearing in this tissue.
  genes:
  - preferred_term: HIF1A
    term:
      id: hgnc:4910
      label: HIF1A
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: DECREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Furthermore, gene set enrichment analysis (GSEA) revealed that the hypoxia pathway is impaired in miR-140G/G, but not in miR-140−/− chondrocytes"
    explanation: >-
      The genotype contrast that assigns the blunted hypoxia response to the acquired arm
      rather than to loss of the microRNA.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Hif1a protein expression was reduced in miR-140G/G chondrocytes"
    explanation: The protein-level measurement behind the node.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "We found that the miR-140 mutant chondrocytes showed a significant reduction of Hif1a, the master transcription factor that regulates energy metabolism in response to hypoxia."
    explanation: >-
      The same finding restated by the group that made it, and the starting point of the
      metabolic branch curated below.
  downstream:
  - target: Reduced Lysyl Oxidase Expression and Collagen Cross-Linking
  - target: Reduced Chondrocyte Glycolysis with Compensatory Mitochondrial Metabolism
- name: Reduced Lysyl Oxidase Expression and Collagen Cross-Linking
  biological_scale: MOLECULAR
  description: >-
    Lysyl oxidases are HIF1A-regulated and are the enzymes that cross-link collagen. Their
    transcripts fall in knock-in chondrocytes and mass spectrometry of rib cartilage from the
    same mice shows the cross-links themselves reduced. LOXL3 is separately one of the
    acquired targets of the mutant seed, so this node is reached both directly and through
    HIF1A.
  genes:
  - preferred_term: LOXL3
    term:
      id: hgnc:13869
      label: LOXL3
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "mRNA expression of Hif1a and Hif1a-regulated molecules including lysyl oxidases, essential for collagen crosslinking, significantly decreased in miR-140G/G chondrocytes, with a concomitant decrease in collagen crosslinking in the rib cartilage"
    explanation: >-
      Transcript and cross-link measurements in the same sentence, which is what makes this a
      structural consequence rather than an expression change alone.
  downstream:
  - target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
- name: Reduced Chondrocyte Glycolysis with Compensatory Mitochondrial Metabolism
  biological_scale: CELLULAR
  description: >-
    HIF1A stimulates glycolysis and restrains mitochondrial metabolism, so its repression
    reverses both. In knock-in chondrocytes glycolytic genes fall while mitochondrial genes
    rise in a dose-dependent way, and Seahorse measurement of extracellular acidification and
    oxygen consumption confirms the reciprocal shift.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  mechanism_confidence: PROVISIONAL
  notes: >-
    This node and the two below it come from a bioRxiv preprint that has not, as of curation,
    appeared in a peer-reviewed journal. The measurements quoted here were made in the miR-140
    mutant itself; the steps below it were established largely in Ldha and Acly conditional
    knockouts used as surrogates, which is recorded on those nodes.
  evidence:
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "We found that the expression of genes whose products of which function is related to energy metabolism was significantly altered; those that regulate glycolysis was reduced, whereas those that regulate mitochondrial function and metabolism were reciprocally upregulated in a dose-dependent manner"
    explanation: >-
      The transcriptomic form of the shift, in primary chondrocytes from the original knock-in
      line, with a gene-dose relationship.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "In this study, we show that the disease-causing GOF mutant miR-140 decreases glycolysis and increases OXPHOS in growth plate chondrocytes, that reduced glycolysis via Ldh ablation increases resting chondrocyte proliferation and reduces histone acetylation, and that Acly disruption causes cellular and molecular abnormalities similar to those of Ldh ablation in chondrocytes."
    explanation: >-
      The paper's own summary, which also states plainly that the middle of the chain was
      tested in Ldh and Acly knockouts rather than in the miR-140 mutant.
  downstream:
  - target: Reduced Acetyl-CoA Availability and Histone Acetylation
- name: Reduced Acetyl-CoA Availability and Histone Acetylation
  biological_scale: MOLECULAR
  description: >-
    Less glycolytic flux means less mitochondria-derived citrate and so less cytoplasmic
    acetyl-CoA, the acetyl donor for histone acetylation. Histone acetylation is reduced both
    in the miR-140 mutant and in Ldha-deficient chondrocytes. Deleting Acly, which converts
    citrate to acetyl-CoA, reproduces the growth plate phenotype without producing an energy
    deficit, which is the experiment that separates the acetyl-CoA explanation from a simple
    ATP shortage.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  mechanism_confidence: PROVISIONAL
  notes: >-
    The step from reduced acetyl-CoA to the growth plate phenotype rests on Acly and Ldha
    conditional knockouts, not on the miR-140 mutant. What the mutant itself contributes is
    the reduced glycolysis and the reduced histone acetylation. The onward step to FGFR3 is
    weaker still and is recorded as an open question rather than as a causal edge.
  evidence:
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We have also found that reduced glycolysis results in reduced histone acetylation in the miR-140 mutant as well as LDH-deficient chondrocytes likely due to the reduction in acetyl-CoA generated from mitochondria-derived citrate."
    explanation: >-
      The measurement in the miR-140 mutant, together with the surrogate model that supports
      the same reading.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Reduction in acetyl-CoA conversion from citrate by deleting Acly caused an expansion of the resting zone and a similar gross phenotype to LDH-deficient bones without inducing energy deficiency, suggesting that the reduced acetyl-CoA, but not the ATP synthesis deficit, is responsible for the increase in resting zone chondrocytes."
    explanation: >-
      The control that makes acetyl-CoA rather than ATP the operative variable, and the source
      of the causal direction on the edge out of this node.
  downstream:
  - target: Resting-Zone Chondrocyte Expansion
- name: Resting-Zone Chondrocyte Expansion
  biological_scale: TISSUE
  description: >-
    The distinctive growth plate lesion of this disease. Resting-zone chondrocytes, the most
    immature population in the growth plate, proliferate more and accumulate, so the resting
    zone and the growth plate as a whole are expanded - in the proximal tibia and in the
    spheno-occipital synchondrosis of the basal skull. Proliferating columnar chondrocytes are
    not similarly affected, and the null mouse does not show the lesion at all.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  locations:
  - preferred_term: growth plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The proximal tibial growth plate also showed an expansion of the resting zone in miR-140G/G and miR-140G/+ mice"
    explanation: >-
      The lesion in the original knock-in line, present in heterozygotes as well as
      homozygotes.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The basal skull growth plate was wider due to the increased length of all layers of chondrocytes in miR-140G/G and miR-140G/+ mice, whereas miR-140−/− mice showed no significant changes"
    explanation: >-
      The same lesion at the cranial base, with the null comparison that assigns it to the
      substitution rather than to loss of the microRNA.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "EdU labeling revealed a significant increase in cell proliferation in resting zone chondrocytes but not in proliferating chondrocytes"
    explanation: >-
      What the expansion consists of - a selective increase in resting-zone proliferation, in
      an enhanced-expression knock-in line.
  - reference: PMID:41242538
    reference_title: "Transcriptomic profiling confirms microRNA-140 is more functional in joint development than in disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Spatial transcriptomics uniquely revealed miR-140-5p's most pronounced functional role to resting chondrocytes and, unexpectedly, the perichondrium."
    explanation: >-
      Independent corroboration, from a different laboratory and a different genotype, that the
      resting zone is where miR-140-5p matters most. Indirect for this node because the model
      is a null rather than the seed substitution, so it locates the microRNA's function
      without demonstrating this allele's lesion.
  downstream:
  - target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
  - target: Widened Cranial Base Growth Plate
- name: Dysregulation of the Chondrocyte Maturation Programme
  biological_scale: CELLULAR
  description: >-
    The two target-repertoire changes and the YBX1 competition converge on a chondrocyte
    transcriptome that is shifted rather than destroyed. Col10a1, the marker of hypertrophic
    maturation, and other extracellular matrix transcripts fall in knock-in chondrocytes.
    Neither proliferation nor apoptosis in the tibial growth plate differs from wild type, so
    the lesion is a failure to mature rather than loss of cells.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    modifier: DYSREGULATED
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  genes:
  - preferred_term: COL10A1
    term:
      id: hgnc:2185
      label: COL10A1
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "In addition, expression of several extracellular matrix genes including Col10a1 decreased in miR-140G/G and miR-140G/+ chondrocytes"
    explanation: >-
      The transcriptional shift, in both mutant genotypes, including the hypertrophic
      maturation marker.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The proliferation rate of tibial growth plate chondrocytes was not significantly different among miR-140G/G, miR-140G/+, and wild-type mice"
    explanation: >-
      A negative result that constrains the mechanism: the growth plate abnormality is not a
      proliferation defect.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We did not find an increased number of apoptotic cells in the growth plate of miR-140G/G mice"
    explanation: "The second negative: it is not cell death either."
  downstream:
  - target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
  - target: Delayed Maturation of Laryngeal, Tracheal and Costal Cartilage
- name: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
  biological_scale: TISSUE
  description: >-
    The tissue-level lesion the radiographs show. Secondary ossification of tubular and carpal
    bones is delayed and epiphyseal mineralization is severely reduced in the knock-in mouse,
    in heterozygotes as well as homozygotes, and the same abnormalities are consistent from
    postnatal day 7 to day 56. Vertebral bodies are mildly flattened. The authors state that
    the mouse findings correspond to the patients' delayed secondary ossification, mild
    platyspondyly, small epiphyses and scaphocephaly.
  biological_processes:
  - preferred_term: endochondral ossification
    modifier: DECREASED
    term:
      id: GO:0001958
      label: endochondral ossification
  locations:
  - preferred_term: secondary ossification center
    term:
      id: UBERON:0010357
      label: secondary ossification center
  - preferred_term: epiphysis
    term:
      id: UBERON:0001437
      label: epiphysis
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "only miR-140G/G and miR-140G/+ mice showed delayed secondary ossification of tubular and carpal bones"
    explanation: >-
      The core skeletal lesion, and the word "only" - the null mice in the same experiment did
      not have it.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Micro-CT analysis showed severely decreased epiphyseal mineralization in miR-140G/G mice"
    explanation: The quantitative imaging measurement of the same lesion.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "These bone abnormalities of miR-140G/G and miR-140G/+ mice are consistent at all analyzed ages from P7 to P56 when compared to wild-type mice"
    explanation: >-
      The mouse half of the correspondence: the same abnormalities at every age examined from
      postnatal day 7 to day 56. The human half of the same sentence is quoted on the
      phenotypes it names.
  downstream:
  - target: Disproportionate Short-Limb Short Stature
  - target: Severe Brachydactyly
  - target: Cone-Shaped Phalangeal Epiphyses
  - target: Delayed Epiphyseal Ossification
  - target: Small Epiphyses
  - target: Small Hands
  - target: Short Feet
  - target: Platyspondyly
  - target: Premature Degeneration of Spine and Joints
- name: Widened Cranial Base Growth Plate
  biological_scale: TISSUE
  description: >-
    The cranial counterpart of the growth plate lesion. The spheno-occipital synchondrosis, a
    bidirectional growth plate in the basal skull, is widened in knock-in mice and not in null
    mice. Cranial base growth sets midfacial projection and skull shape, which is the route by
    which a chondrocyte disease produces midface hypoplasia, a small nose and scaphocephaly.
  locations:
  - preferred_term: growth plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  mechanism_confidence: PROVISIONAL
  notes: >-
    The widened synchondrosis is measured; the step from it to the patients' craniofacial
    features is an anatomical inference, not a demonstration. No craniofacial morphometry has
    been reported in either the mice or the patients, which is why the node is PROVISIONAL.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The basal skull growth plate was wider due to the increased length of all layers of chondrocytes in miR-140G/G and miR-140G/+ mice, whereas miR-140−/− mice showed no significant changes"
    explanation: The measurement, with the null comparison.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In the spheno-occipital synchondrosis, a bidirectional growth plate in the basal skull, showed an expansion of the resting zone"
    explanation: >-
      Identifies the structure by name and attributes the widening to the same resting-zone
      expansion seen in the tibia. Quoted from the Ldha knockout arm of the preprint, so it
      supports the anatomy and the lesion type rather than the miR-140 genotype specifically.
  downstream:
  - target: Midface Hypoplasia
  - target: Short Nose
  - target: Scaphocephaly
- name: Delayed Maturation of Laryngeal, Tracheal and Costal Cartilage
  biological_scale: TISSUE
  description: >-
    Cartilage maturation is delayed outside the growth plate as well. Alizarin red staining
    shows delayed maturation of the larynx, trachea and anterior ribs in knock-in mice. In the
    two patients of Family 1 this corresponds to inspiratory stridor and recurrent respiratory
    infection, and in the proband to a narrow larynx attributed to floppy cartilage on
    fiberscopy.
  locations:
  - preferred_term: larynx
    term:
      id: UBERON:0001737
      label: larynx
  - preferred_term: trachea
    term:
      id: UBERON:0003126
      label: trachea
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "decreased expression of Col10a1, a maturation marker for hypertrophic chondrocytes (Extended Data Fig. 3b), and delayed cartilage maturation of the larynx, trachea, and anterior ribs"
    explanation: >-
      Names the three extraskeletal cartilages involved, alongside the maturation marker that
      falls with them.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 had a narrow larynx likely due to floppy cartilage"
    explanation: >-
      The human counterpart, and the clinicians' own attribution of the airway finding to
      cartilage rather than to a neuromuscular or infectious cause.
  downstream:
  - target: Laryngomalacia
  - target: Inspiratory Stridor
  - target: Recurrent Respiratory Infections
- name: Premature Degeneration of Spine and Joints
  biological_scale: ORGANISM
  description: >-
    The adult phase. The spondylar and epiphyseal abnormalities of childhood do not stabilise:
    they progress to premature spondylosis and degenerative joint disease. Reduced collagen
    cross-linking in cartilage is a plausible contributor, and independently miR-140-null mice
    develop age-related osteoarthritis-like change, but no joint tissue from a patient has been
    examined and the molecular bridge is not established.
  mechanism_confidence: PROVISIONAL
  notes: >-
    The clinical outcome is reported; the mechanism connecting it to the upstream nodes is
    not. The cross-linking deficit and the null mouse osteoarthritis are both suggestive and
    neither was measured in this disease, which is what PROVISIONAL records here.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spondylar and epiphyseal abnormalities evolved into premature spondylosis and degenerative joint disease in adulthood, respectively."
    explanation: The observed adult course in the reported patients.
  - reference: PMID:20466812
    reference_title: "MicroRNA-140 plays dual roles in both cartilage development and homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Interestingly, miR-140(-/-) mice showed age-related OA-like changes characterized by proteoglycan loss and fibrillation of articular cartilage."
    explanation: >-
      Establishes that miR-140 has a joint-maintenance role independent of development.
      Indirect for this node because the genotype is a null, not the seed substitution, so it
      shows that the pathway matters for joints without showing that this allele acts through
      it.
  - reference: PMID:41242538
    reference_title: "Transcriptomic profiling confirms microRNA-140 is more functional in joint development than in disease."
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, its influence on post-traumatic OA is modest, with limited impact on cartilage degeneration but a role in modulating osteophyte formation."
    explanation: >-
      The counterweight, and the reason this node is not built on the osteoarthritis
      literature. A newer null mouse subjected to destabilisation of the medial meniscus shows
      only a modest increase in cartilage damage, with no enrichment of predicted miR-140-5p
      targets among the upregulated genes. Graded NO_EVIDENCE for this node because it neither
      supports nor refutes a claim about the seed allele - it constrains how much the null
      mouse osteoarthritis result can be leaned on.
  downstream:
  - target: Premature Osteoarthritis
phenotypes:
- name: Disproportionate Short-Limb Short Stature
  category: Growth
  description: >-
    Short stature with disproportionately short limbs, present in all three reported
    individuals and the presenting feature of the disorder.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  notes: >-
    Frequency here and on the other core skeletal features is a description of a three-patient
    series, not a population estimate. The source states these as the clinical features of the
    disorder rather than giving a per-patient count, so VERY_FREQUENT is used in preference to
    OBLIGATE, which would assert complete penetrance from three observations.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."
    explanation: The clinical description of the entity, from the report that defined it.
- name: Small Hands
  category: Limbs
  frequency: VERY_FREQUENT
  description: Small hands, described together with the small feet and the brachydactyly.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."
    explanation: The clinical description of the entity, from the report that defined it.
- name: Short Feet
  category: Limbs
  frequency: VERY_FREQUENT
  description: Small feet, reported alongside the small hands.
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  notes: >-
    The source says "small hands and feet". HP:0001773 Short foot is the closest available
    term; HPO has no "small foot" concept matching the hand term, so the binding trades
    exactness of wording for an existing term rather than manufacturing a narrower match.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."
    explanation: The clinical description of the entity, from the report that defined it.
- name: Severe Brachydactyly
  category: Limbs
  frequency: VERY_FREQUENT
  description: >-
    Severe shortening of the digits, one of the three radiological hallmarks of the disorder
    and the feature that raises acrodysostosis as a differential.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
    severity: SEVERE
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"
    explanation: The three radiological hallmarks, stated together, including the severity qualifier.
- name: Cone-Shaped Phalangeal Epiphyses
  category: Limbs
  frequency: VERY_FREQUENT
  description: Cone-shaped epiphyses of the phalanges, reported together with the brachydactyly.
  phenotype_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"
    explanation: The three radiological hallmarks, stated together.
- name: Delayed Epiphyseal Ossification
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >-
    Delayed epiphyseal ossification, specified at the hip and knee. This is the feature that
    most sharply separates the disorder from acrodysostosis, where carpal ossification is
    advanced rather than delayed.
  phenotype_term:
    preferred_term: Delayed epiphyseal ossification
    term:
      id: HP:0002663
      label: Delayed epiphyseal ossification
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"
    explanation: The three radiological hallmarks, stated together.
- name: Small Epiphyses
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Small epiphyses, listed among the patients' features in the mouse-to-human comparison.
  phenotype_term:
    preferred_term: Small epiphyses
    term:
      id: HP:0010585
      label: Small epiphyses
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"
    explanation: >-
      The patient feature list given when the authors compare their mice with the humans. The
      clause quoted is the human half of that comparison.
- name: Platyspondyly
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >-
    Mild spondylar dysplasia radiographically, described as mild platyspondyly when the
    patients' features are compared with the mouse.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
    severity: MILD
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"
    explanation: >-
      The word platyspondyly applied to the patients, with the mild qualifier that the
      severity slot records.
- name: Midface Hypoplasia
  category: Head and Neck
  frequency: VERY_FREQUENT
  description: Midface hypoplasia, part of the facial appearance of the disorder.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."
    explanation: The clinical description of the entity, from the report that defined it.
- name: Short Nose
  category: Head and Neck
  frequency: VERY_FREQUENT
  description: A small nose, reported as part of the midface hypoplasia.
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose."
    explanation: The clinical description of the entity, from the report that defined it.
- name: Scaphocephaly
  category: Head and Neck
  frequency: VERY_FREQUENT
  description: >-
    A long, narrow skull shape, listed among the patients' features. Consistent with a cranial
    base growth plate abnormality rather than with premature suture fusion, although no
    craniofacial imaging analysis has been published.
  phenotype_term:
    preferred_term: Scaphocephaly
    term:
      id: HP:0030799
      label: Scaphocephaly
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"
    explanation: The patient feature list in the mouse-to-human comparison.
- name: Laryngomalacia
  category: Respiratory
  frequency: FREQUENT
  description: >-
    A narrow larynx attributed to floppy cartilage, found on fiberscopy in the proband at 44
    years of age, with an enlarged right arytenoid cartilage prolapsing over the larynx on
    inspiration.
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  notes: >-
    FREQUENT rather than VERY_FREQUENT because the airway findings are reported for the two
    members of Family 1 and not for the third patient, and the fiberscopic diagnosis is
    documented for one individual only.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 had a narrow larynx likely due to floppy cartilage"
    explanation: The finding and its attribution to cartilage.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fiberscopy findings in P1, 44 years of age, consistent with laryngomalacia."
    explanation: >-
      The endoscopic diagnosis in the term used by HPO, with the age at which it was made.
- name: Inspiratory Stridor
  category: Respiratory
  frequency: FREQUENT
  description: Inspiratory stridor in the mother and son of Family 1, with prolonged cough.
  phenotype_term:
    preferred_term: Inspiratory stridor
    term:
      id: HP:0005348
      label: Inspiratory stridor
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 and P2 also suffered from frequent respiratory infections with prolonged cough and inspiratory stridor."
    explanation: The airway symptoms and the two individuals in whom they were recorded.
- name: Recurrent Respiratory Infections
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Frequent respiratory infections in the two members of Family 1, plausibly secondary to the
    airway cartilage abnormality rather than to an immune defect - basic blood tests were
    normal in all three patients.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 and P2 also suffered from frequent respiratory infections with prolonged cough and inspiratory stridor."
    explanation: The infections and the individuals in whom they occurred.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three affected individuals had normal intelligence, dentition, hearing, visual acuity, and basic blood tests."
    explanation: >-
      The negative that argues against an immunological explanation, and separately records
      that the disorder is not syndromic beyond the skeleton and airway.
- name: Premature Osteoarthritis
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Degenerative joint disease and premature spondylosis developing in adulthood out of the
    childhood epiphyseal and spondylar abnormalities.
  phenotype_term:
    preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  notes: >-
    FREQUENT rather than VERY_FREQUENT because this is an adult-onset feature and only one of
    the three reported patients was an adult at the time of the report; the youngest is a
    child. It is a statement about the disorder's course rather than a count of affected
    individuals.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spondylar and epiphyseal abnormalities evolved into premature spondylosis and degenerative joint disease in adulthood, respectively."
    explanation: The adult outcome of the two childhood radiographic abnormalities.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No prevalence estimate exists. Three affected individuals in two unrelated families have
    been reported, in a single 2019 paper, and no further patient has appeared in the
    literature since. The families were ascertained through a project specifically directed at
    ultra-rare congenital skeletal disorders, which is a selected denominator rather than a
    population one. prevalence_class is the qualitative ULTRA_RARE tier and no
    rate_per_100000 is given, because none has been reported and a numeric band beside this
    note would be an invention.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel skeletal dysplasia was identified in two unrelated families in a project for molecular diagnosis of ultra-rare congenital skeletal disorders"
    explanation: The number of families and the ascertainment route that found them.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We previously reported that a single nucleotide substitution of the MIR140 in humans caused ultra-rare skeletal dysplasia, spondyloepiphyseal dysplasia, Nishimura type"
    explanation: >-
      The same group calling the disorder ultra-rare four years later, which is the closest
      thing to a rarity statement that exists. Graded OTHER because it is a preprint's
      introduction restating its own earlier human genetics rather than reporting patients.
progression:
- phase: Childhood skeletal dysplasia
  notes: >-
    Disproportionate short stature, brachydactyly with cone-shaped epiphyses, delayed
    epiphyseal ossification and mild spondylar dysplasia are the childhood picture. In Family
    1 the airway symptoms - prolonged cough and inspiratory stridor - are also present in this
    phase. No age at onset, growth velocity or bone-age series is quotable: auxology data are
    in a supplementary table that the cached record does not carry.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses"
    explanation: The radiographic features that define the childhood phase.
- phase: Adult degenerative phase
  notes: >-
    The skeletal abnormalities do not remain static after growth ends. Spondylar dysplasia
    progresses to premature spondylosis and the epiphyseal abnormalities to degenerative joint
    disease. Bone density was normal for age in the proband at 43, so this is a structural and
    degenerative course rather than a bone-mass disorder. Survival to at least the mid-forties
    is documented, and there is no report of a lethal outcome.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spondylar and epiphyseal abnormalities evolved into premature spondylosis and degenerative joint disease in adulthood, respectively."
    explanation: The adult course, stated for the reported patients.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had normal bone density for the age, which suggests that the heterozygous MIR140 mutation in humans does not lead to bone mass abnormalities."
    explanation: >-
      The one quantitative adult measurement published, and the negative it establishes: this
      is not a bone-fragility disorder.
genetic:
- name: MIR140
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: MIR140
    term:
      id: hgnc:31527
      label: MIR140
  notes: >-
    MIR140 is a microRNA gene, HGNC locus type "RNA, micro", at 16q22.1 within an intron of
    WWP2 and associated with a chondrocyte-specific super-enhancer. It has no protein product,
    so the vocabulary usually attached to a Mendelian gene - missense, nonsense, truncating,
    dominant negative, a PDB structure, a molecular function term for a gene product - does
    not apply. The unit of pathogenicity is one nucleotide of a 22-nucleotide mature RNA.

    Only one pathogenic allele is known, n.24A>G, and it is the same in both families. Unlike
    MIR96, where three alleles at three positions define two mechanistically distinct classes,
    there is no allelic series here to reason from.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because the phenotype has not been reported previously and these patients were found to have the same variant in the MIR140 gene, we propose the eponym of spondyloepiphyseal dysplasia (SED) MIR140 type Nishimura."
    explanation: >-
      The gene-disease relationship as established, and the origin of the disorder's name.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening P1, P2, and P3 for possible disease causing variants in 378 known skeletal dysplasia genes using WGS data, and screening P2 for gene dose abnormalities of the above mentioned skeletal dysplasia genes using custom-designed comparative genome hybridization analysis was all negative"
    explanation: >-
      The exclusion work behind the gene assignment: 378 known skeletal dysplasia genes and a
      dosage screen, all negative, before MIR140 was implicated.
diagnosis:
- name: MIR140 sequencing in an unexplained spondyloepiphyseal dysplasia with brachydactyly
  description: >-
    The route to this diagnosis is radiographic recognition followed by sequencing that
    actually covers MIR140. The practical trap is structural: MIR140 is a short non-coding
    gene, so an exome pipeline built around coding exons will not find the variant. In both
    families exome sequencing was performed first and returned nothing in the protein-coding
    genes; whole genome sequencing, searching non-coding as well as coding genes, found the
    substitution. A panel of 378 known skeletal dysplasia genes and a dosage array were also
    negative. Once the entity was recognised in the second family, Sanger sequencing of MIR140
    was sufficient.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No potential disease causing variants were found in the protein coding genes."
    explanation: >-
      The exome result in both families, and the reason a coding-only analysis will miss this
      diagnosis.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole genome sequencing (WGS) identified the same heterozygous nucleotide substitution (chr16:g.69967007A>G (hg19), MIR140:NR_029681.1:n.24A>G) in P1 and P2"
    explanation: The test that made the diagnosis, and the variant nomenclature to report.
differential_diagnoses:
- name: Acrodysostosis
  description: >-
    The differential the authors single out. Both disorders combine midface hypoplasia with
    brachydactyly and cone-shaped epiphyses, so the hands and face look similar. Two things
    separate them. Epiphyseal maturation is delayed in SED Nishimura type and advanced,
    particularly in the carpus, in acrodysostosis - the ossification clock runs the opposite
    way. And epiphyseal dysplasia, which is a hallmark here, is not a feature of
    acrodysostosis. The reported patients also had none of the endocrine abnormalities of
    acrodysostosis and no PDE4D or PRKAR1A variant.
  distinguishing_features:
  - Delayed rather than advanced epiphyseal and carpal ossification
  - Epiphyseal dysplasia, which acrodysostosis does not have
  - No hypocalcaemia, hyperphosphataemia, raised PTH or TSH, or low IGF-1
  - No PDE4D or PRKAR1A variant
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present disorder should be differentiated from acrodysostosis."
    explanation: The authors naming the differential.
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, epiphyseal maturation is delayed in SED MIR140 type Nishimura, whereas epiphyseal ossification, particularly carpal ossification, is advanced in acrodysostosis."
    explanation: The single most useful discriminator, and the direction it runs in.
animal_models:
- name: Mir140 n.24A>G knock-in mouse
  species: Mouse
  genotype: Mir140 A>G knock-in (the human n.24A>G substitution), heterozygous and homozygous
  background: C57BL/6, two independent CRISPR-Cas9 founder lines
  publication: PMID:30804514
  genes:
  - preferred_term: MIR140
    term:
      id: hgnc:31527
      label: MIR140
  description: >-
    The model that carries the argument. CRISPR-Cas9 was used to introduce the patients' exact
    substitution into the mouse genome, and two independent founder lines gave the same
    phenotype. Heterozygotes, the genotype a patient has, show delayed secondary ossification,
    a widened basal skull growth plate, an expanded resting zone and mildly flattened
    vertebral bodies; homozygotes are more severely affected. The whole force of the model is
    the side-by-side comparison with miR-140-null mice, which do not have these features.
  modeled_mechanisms:
  - target: Repression of Novel Targets Acquired by the Mutant Seed
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The chondrocyte transcriptome of this line is where the acquired target set was
      demonstrated, and where it was shown to be absent from the null.
    limitations: >-
      The acquired target set is defined in mouse chondrocytes and predicted by TargetScan; no
      human chondrocyte or patient cartilage has been profiled, so the specific transcripts
      repressed in a patient are inferred from orthology rather than measured. Repression of
      the acquired set was strongest for 8mer sites, so the reported effect is weighted
      towards the best-predicted subset.
    readouts:
    - name: Expression of predicted mutant-seed target genes
      target: Repression of Novel Targets Acquired by the Mutant Seed
      direction: DECREASED
      interpretation: >-
        Transcripts carrying a match to the mutant seed fall, and do so only in genotypes
        carrying the substitution.
      evidence:
      - reference: PMID:30804514
        reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Importantly, the widespread suppression of predicted miR-140-5p-G targets is only observed in miR-140G/G and miR-140G/+ chondrocytes"
        explanation: The measurement and the genotype restriction that makes it informative.
    evidence:
    - reference: PMID:30804514
      reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects."
      explanation: >-
        Establishes that this model is the system in which both arms of the mechanism were
        shown, which is what makes it informative for this node.
  - target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Heterozygous knock-in mice have delayed secondary ossification of tubular and carpal
      bones and severely reduced epiphyseal mineralization, which the authors map directly onto
      the patients' delayed secondary ossification and small epiphyses.
    limitations: >-
      The correspondence between mouse and human is asserted by inspection of radiographs and
      histology rather than by a quantified morphometric comparison. Homozygous mice, in which
      the lesion is most severe, have no human counterpart - no homozygous patient has been
      reported. The mouse work was done on a single background, C57BL/6, and the timing of the
      mouse lesion is postnatal weeks against a human course measured in years.
    readouts:
    - name: Secondary ossification of tubular and carpal bones
      target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
      direction: DECREASED
      interpretation: >-
        Ossification centres appear late, in heterozygotes as well as homozygotes, and not in
        null mice.
      evidence:
      - reference: PMID:30804514
        reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "only miR-140G/G and miR-140G/+ mice showed delayed secondary ossification of tubular and carpal bones"
        explanation: The readout and the genotypes in which it is seen.
    - name: Epiphyseal mineralization by micro-computed tomography
      target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
      direction: DECREASED
      interpretation: Mineral content of the epiphysis is severely reduced in homozygotes.
      evidence:
      - reference: PMID:30804514
        reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Micro-CT analysis showed severely decreased epiphyseal mineralization in miR-140G/G mice"
        explanation: The quantitative imaging readout.
    evidence:
    - reference: PMID:30804514
      reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These bone abnormalities of miR-140G/G and miR-140G/+ mice are consistent at all analyzed ages from P7 to P56 when compared to wild-type mice"
      explanation: >-
        The mouse side of the model-to-patient correspondence: the lesion is stable across
        every age examined rather than a transient developmental lag.
    - reference: PMID:30804514
      reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly"
      explanation: >-
        The human side of the same sentence, and what makes this model informative for the
        node: the patient features the mouse lesion is said to correspond to. Graded
        HUMAN_CLINICAL because the clause reports the authors' own patients.
  - target: Resting-Zone Chondrocyte Expansion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The proximal tibial growth plate and the basal skull growth plate are both expanded, and
      the expansion is in the resting zone. This is the lesion the later metabolic work was
      built to explain.
    limitations: >-
      Fidelity is MODERATE rather than HIGH because no human growth plate has ever been
      examined in this disease: the resting-zone lesion is a mouse finding whose human
      counterpart is inferred from the radiographic delay in ossification. The follow-up work
      also had to build an enhanced-expression line, with additional nucleotide changes that
      no patient carries, to make the phenotype robust in heterozygotes.
    readouts:
    - name: Resting zone width of the proximal tibial growth plate
      target: Resting-Zone Chondrocyte Expansion
      direction: INCREASED
      interpretation: The resting zone is expanded in heterozygotes and homozygotes.
      evidence:
      - reference: PMID:30804514
        reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The proximal tibial growth plate also showed an expansion of the resting zone in miR-140G/G and miR-140G/+ mice"
        explanation: The readout and its direction.
    evidence:
    - reference: PMID:36711926
      reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the mouse model carrying the identical substitution as in patients, the resting zone of the growth plate was expanded, causing a delay in ossification and development of the epiphysis."
      explanation: >-
        The later paper stating what this model established and why the resting-zone lesion is
        taken to explain the ossification delay.
- name: miR-140-null mouse
  species: Mouse
  genotype: Mir140 targeted deletion, heterozygous and homozygous
  publication: PMID:21576357
  genes:
  - preferred_term: MIR140
    term:
      id: hgnc:31527
      label: MIR140
  description: >-
    Not a model of this disease but the control that defines it. Deleting the microRNA gives
    dwarfism and craniofacial deformity with mildly accelerated hypertrophic differentiation -
    a phenotype that overlaps the knock-in in stature and face but is opposite in the growth
    plate, where maturation is advanced rather than delayed. Null mice also develop
    age-related osteoarthritis-like change. Heterozygous nulls are normal.
  modeled_mechanisms:
  - target: Loss of Repression of Wild-Type miR-140-5p Targets
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      A deletion reproduces the abandoned half of the mechanism exactly, since removing the
      microRNA is the cleanest possible way to de-repress its normal targets. It is the
      reference against which the knock-in transcriptome was read.
    limitations: >-
      It reproduces only that half. A null allele cannot acquire targets, so nothing measured
      in this line speaks to the neomorphic arm, and features shared between null and knock-in
      cannot be attributed to either arm on the strength of this model alone.
    readouts:
    - name: Expression of conserved wild-type miR-140-5p 8mer target genes
      target: Loss of Repression of Wild-Type miR-140-5p Targets
      direction: INCREASED
      interpretation: >-
        Normal targets rise in the deletion just as they do in the knock-in, which is what
        makes this arm the shared one.
      evidence:
      - reference: PMID:30804514
        reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Both the miR-140 A>G mutation and miR-140 deletion caused derepression of conserved 8mer target genes for wild-type miR-140-5p and to a lesser extent for miR-140-3p species"
        explanation: The direct comparison of the two genotypes on the same target set.
    evidence:
    - reference: PMID:21576357
      reference_title: "Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this paper, we show that loss of Mir140 in mice causes growth defects of endochondral bones, resulting in dwarfism and craniofacial deformities."
      explanation: >-
        Establishes what losing the microRNA does on its own, which is the baseline the
        knock-in is compared against.
  - target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The null mouse does not reproduce the disease's defining skeletal lesion. It does not
      have the delayed secondary ossification, and its growth plate runs the other way:
      endochondral bone development is mildly advanced, with accelerated hypertrophic
      differentiation. This negative is the load-bearing result of the entry - it is why the
      substitution is read as neomorphic rather than as a loss of function.
    limitations: >-
      The failure is specific and not total: the null does reproduce the short stature and
      craniofacial abnormality, so it is informative for those features and for the abandoned
      target set. The comparison also has a confound worth stating - the null was made by
      targeted deletion in an earlier study and the knock-in by CRISPR-Cas9 in this one, so
      the two lines differ in provenance as well as in allele, and the phenotypes were scored
      across studies as well as within one.
    readouts:
    - name: Timing of hypertrophic chondrocyte differentiation
      target: Delayed Endochondral Ossification of Epiphyses and Tubular Bones
      direction: INCREASED
      interpretation: >-
        Terminal differentiation is mildly advanced in the null, the opposite direction to the
        delay seen in the knock-in and in patients.
      evidence:
      - reference: PMID:21576357
        reference_title: "Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Endochondral bone development is mildly advanced due to accelerated hypertrophic differentiation of chondrocytes in Mir140-null mice."
        explanation: The direction of the null's growth plate phenotype, in the null paper's own words.
    evidence:
    - reference: PMID:30804514
      reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Taken together, these differences in phenotype between miR-140G/G and miR-140−/− mice, and delayed epiphyseal maturation in humans, indicate that this single-base substitution causes a neomorphic, and not just loss-of-function, effect."
      explanation: >-
        The inference the failure supports, stated by the authors: a null and this allele are
        not the same lesion.
datasets:
- accession: geo:GSE98309
  title: miR-140 mutation and skeletal dysplasia
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:30804514
  genes:
  - preferred_term: MIR140
    term:
      id: hgnc:31527
      label: MIR140
  notes: >-
    The transcriptomic and seCLIP data behind the founding study: primary rib chondrocytes
    from wild-type, knock-in and null mice. It is the dataset in which both arms of the
    mechanism are visible in one experiment. No evidence block, because an evidence item needs
    an exact quote supporting a specific claim and this record asserts only that the dataset
    exists and what it contains.
- accession: geo:GSE192971
  title: Regulatory role of energy metabolism in skeletal development
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:36711926
  notes: >-
    RNA-seq from Ldha and Acly conditional-knockout chondrocytes, the surrogate models used to
    test the metabolic branch. Relevant to this disease as the evidence base for the
    acetyl-CoA account rather than as a measurement of the miR-140 genotype.
discussions:
- discussion_id: sedn_no_human_tissue
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Repression of Novel Targets Acquired by the Mutant Seed"
  - "pathophysiology#Resting-Zone Chondrocyte Expansion"
  prompt: >-
    Does the mutant seed repress the same transcripts in a human chondrocyte that it represses
    in a mouse one, and does a patient growth plate have the expanded resting zone?
  rationale: >-
    Every mechanistic measurement in this entry was made in mouse cells or mouse bone. That is
    not a criticism of the work - the knock-in carries the patients' exact substitution and
    the mature miR-140-5p sequence is conserved - but it leaves two specific things unmeasured
    in humans, and they are not the same kind of gap.

    The acquired target set is the first. It was predicted by TargetScan and confirmed against
    the mouse transcriptome. Because the seed is newly created, its targets have no
    evolutionary history with it, so there is no reason to expect the 3-prime UTR matches to
    be conserved between mouse and human the way the wild-type target set is - the founding
    study itself reports that mutant-seed target sites are less conserved than wild-type ones.
    A human chondrocyte could therefore carry a materially different acquired target set from
    the mouse. Nothing about that has been tested.

    The resting-zone expansion is the second, and it is a gap of a different kind: no human
    growth plate from a patient has been examined at all. The human evidence is radiographic
    delay in ossification, which is compatible with the mouse lesion but does not demonstrate
    it. Since the resting-zone phenotype is what the entire metabolic branch was built to
    explain, its human status matters more than its position in the entry suggests.

    Neither gap can be closed with the existing patients without cartilage, which is not
    ordinarily biopsied. Patient-derived induced pluripotent stem cells differentiated to
    chondrocytes would answer the first question and are within reach; the second may not be
    answerable at all outside an incidental surgical specimen.
  evidence:
  - reference: PMID:30804514
    reference_title: "Gain-of-function mutation of microRNA-140 in human skeletal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Target sites of miR-140-5p-G seldom overlapped with those of wild-type miR-140 species (wild-type 5p, 3p.1, and 3p.2) and were less conserved than those of wild-type miR-140 species"
    explanation: >-
      The specific reason the mouse acquired target set may not transfer: those sites are the
      less conserved ones, so cross-species inference is weaker here than for the wild-type
      set.
- discussion_id: sedn_metabolic_branch_is_provisional
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - "pathophysiology#Reduced Acetyl-CoA Availability and Histone Acetylation"
  - "pathophysiology#Resting-Zone Chondrocyte Expansion"
  prompt: >-
    Does reduced acetyl-CoA in miR-140 mutant chondrocytes cause the resting-zone expansion,
    and does it do so by raising FGFR3?
  rationale: >-
    The metabolic branch of this entry is attractive and incompletely demonstrated, and it is
    worth being exact about which links are which.

    Measured in the miR-140 mutant itself: HIF1A falls, glycolytic gene expression falls,
    mitochondrial gene expression rises, the Seahorse assay confirms the reciprocal shift, and
    histone acetylation falls. Measured in surrogates: that suppressing glycolysis by deleting
    Ldha, or blocking acetyl-CoA synthesis by deleting Acly, expands the resting zone and
    increases resting chondrocyte proliferation. The Acly result is the good control, because
    it separates acetyl-CoA from ATP supply, which a glycolysis block alone would not.

    What has not been done is the experiment in the middle: nobody has restored acetyl-CoA in a
    miR-140 mutant and asked whether the resting zone normalises. Until that is done, the
    identity of the mechanism in the mutant with the mechanism in the knockouts is an
    inference from phenotypic similarity.

    The onward step to FGFR3 is weaker again and is deliberately not curated as a causal edge.
    Fgfr3 is upregulated in both knockouts and a constitutively active FGFR3 expands the
    resting zone, which makes it a good candidate, but the authors write that the mechanism by
    which acetyl-CoA deficiency would raise Fgfr3 is not clear, and no chromatin measurement at
    the Fgfr3 locus has been reported. A causal edge here would assert more than the source
    does. It is also worth noting the irony that would follow if it held: an FGFR3 gain of
    signalling is the mechanism of achondroplasia, reached in this disease by an entirely
    different route.

    A further caveat applies to the whole branch. Its source is a bioRxiv preprint that had not
    appeared in a peer-reviewed journal as of curation, and it has not been independently
    replicated.
  evidence:
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, the mechanism by which Ac-CoA deficiency can lead to the Fgfr3 upregulation and these phenotypic changes is not clear at the moment."
    explanation: >-
      The authors declining to claim the step this entry declines to curate. It is why the
      FGFR3 arm is a discussion rather than an edge.
  - reference: PMID:36711926
    reference_title: "Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data demonstrate the association between reduced glycolysis and an expansion of the resting zone and suggest that it is caused by acetyl-CoA deficiency, but not energy deficiency, possibly through epigenetic upregulation of FGFR3 signaling."
    explanation: >-
      The strength of claim the paper itself makes, with its two hedges - "suggest" and
      "possibly" - which the curation follows.
  proposed_experiments:
  - experiment_id: exp_sedn_acetyl_coa_rescue
    name: Restore acetyl-CoA in miR-140 knock-in chondrocytes and rescore the growth plate
    description: >-
      Supply acetate or citrate, or overexpress Acly, in Mir140 knock-in mice or their primary
      chondrocytes and measure histone acetylation, Fgfr3 expression, resting-zone width and
      resting chondrocyte proliferation against untreated mutants. A rescue would convert the
      acetyl-CoA account of this disease from a phenotypic parallel between three mouse lines
      into a demonstrated mechanism.
- discussion_id: sedn_no_treatment
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  prompt: >-
    Is there any treatment to curate for this disorder?
  rationale: >-
    No, and this entry deliberately has no treatments block. No disease-modifying therapy
    exists, none has been proposed in the literature, and no clinical trial keyed to MIR140 or
    to this disorder was found. Nor has any intervention been tested in the mouse models: the
    knock-in line has been used for mechanism and never as a therapeutic testbed, which is a
    difference from the MIR96 entry, where preclinical gene editing and a repurposed drug are
    curated as rescue links on a mouse model.

    General management of a skeletal dysplasia - orthopaedic and spinal surveillance, pain and
    joint management, physiotherapy, airway assessment where there is stridor, genetic
    counselling - is what these patients will receive in practice, and none of it is reported
    for these three individuals. Importing it would attribute to them an experience recorded
    only of other people with other skeletal dysplasias, and in the exported graph a borrowed
    management statement is indistinguishable from an observed one.

    Closing this gap needs no new science, only a follow-up report on the patients already
    identified.
notes: >-
  Scope decision: curated as a DISEASE. One gene, one recurrent allele, one conserved
  pathograph running from a MIR140 seed substitution to a spondyloepiphyseal dysplasia, and no
  member diseases to unite - so neither a grouping nor a subtype of anything curated here. Its
  MONDO parent, MONDO:0016761 spondyloepiphyseal dysplasia, is an ontology grouping of dozens
  of unrelated SED loci and is not a dismech entry. The stub is deleted by this change, which
  is how a DISEASE decision is recorded.

  On the relationship to the MIR96 entry. Autosomal_Dominant_Nonsyndromic_Hearing_Loss_50 is
  the knowledge base's other microRNA disease and settled several modelling questions this
  entry inherits. Two are followed and one is not. Followed: the miRNA GeneDescriptor needs no
  special shape, since GeneTerm carries no reachable_from constraint; and modifier is left
  absent on the acquired-target node, because what changed is the specificity of the silencing
  and not its level. Not followed: functional_impact_category is set to NEOMORPHIC here rather
  than left absent, and the reason is set out in full on the genetic_context of the first
  pathophysiology node. In short, the MIR140 mouse comparison assigns the disease-defining
  features to the acquired arm in a way the MIR96 work does not, and the founding authors use
  the word "neomorphic" of this allele in a sentence quoted in the entry. The two entries
  should be read as disagreeing deliberately rather than inconsistently.

  What is deliberately not curated. There is no treatments block; the reasoning is in the
  discussion sedn_no_treatment. There is no biochemical, histopathology, imaging or
  clinical_trials content, because no human material or trial of that kind exists for these
  three patients. There is no environmental block: this is a de novo germline substitution and
  no exposure has been proposed. Detailed auxology - birth and follow-up z-scores, age at
  onset, growth velocity - is in Supplementary Table 1 of the founding paper, which the
  reference cache does not carry, so no numeric growth data is quoted rather than taken
  second-hand.

  On module conformance. Two modules look like a fit and neither is declared.
  fgfr_gain_of_function_skeletal_dysplasia has a growth-plate dysregulation node and an
  impaired-endochondral-ossification node that would take this entry's nodes almost verbatim,
  and the metabolic branch curated here even ends in Fgfr3 upregulation - but that module's own
  notes scope it to germline FGFR gain-of-function alleles and enumerate the intended
  conformers, and this disease has no FGFR variant. osteoarthritis_cartilage_degradation will
  dominate any naive miR-140 literature search, because the microRNA has a large osteoarthritis
  literature, and it is also wrong here: the one adult patient's degenerative joint disease is
  secondary damage to a dysplastic joint, not the mechanism, and PMID:41242538 reports that
  miR-140's influence on post-traumatic osteoarthritis is modest. That paper is cited on the
  joint node as NO_EVIDENCE for exactly that reason. There is no generic growth-plate or
  endochondral-ossification module in kb/modules/ for this entry to conform to, which is a
  gap worth its own proposal rather than something to build inside a curation PR.

  On the ISDS nosology. Every other skeletal dysplasia entry in this knowledge base carries an
  isds_skeletal_category classification with a "listed as" note naming the nosology table row.
  This entry carries none. The cached record of the 2023 nosology, PMID:36779427, is the
  abstract and reference list only - it contains no occurrence of MIR140 and none of the
  disease tables - and the 2019 revision is cached as an abstract too. Group 13,
  spondyloepi(meta)physeal dysplasias, is where the disorder would plausibly sit, but placing
  it there without seeing the table would be a guess dressed as a classification, and the
  other entries' notes make a claim about a specific table row that could not be honoured here.

  On identifiers. MONDO:0032835 cross-references OMIM 618618, MedGen 930816, DOID 0112288, GARD
  0025756 and UMLS C4305147. It has no Orphanet cross-reference, and the Orphanet API returns
  no record for this disorder. Two identifier errors in the sources are worth recording so they
  are not propagated. The deep-research report committed with this entry gives ORPHA:163649 for
  this disease; that code is Spondyloepiphyseal dysplasia-craniosynostosis-cleft
  palate-cataracts-intellectual disability syndrome, a different disorder, and it is not used
  here. Separately, PMID:36711926 gives the OMIM number as 611894 in both its abstract and its
  introduction, where the MONDO cross-reference and the founding paper give 618618; only the
  latter is used.

  On the deep-research report. research/Spondyloepiphyseal_Dysplasia_Nishimura_Type-deep-research-falcon.md
  is committed with this entry. Its Named Entity Confusion preflight passes: MIR140 is
  mentioned 54 times against 10 for the next gene, and the OMIM number it reports matches the
  one MONDO cross-references. Its main contribution was to surface PMID:36711926, the metabolic
  follow-up, which a search on the disease name alone does not return. Its identifier error is
  described above; the obsolete GO:0016573 it suggested for histone acetylation is not used,
  and every ontology term in this entry was resolved through OLS and checked against the label
  the service returned rather than against the label the report wrote.

📚

References & Deep Research

References

7

PMID:30804514

Gain-of-function mutation of microRNA-140 in human skeletal dysplasia.

No top-level findings curated for this source.

PMID:36711926

Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate.

No top-level findings curated for this source.

PMID:21576357

Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling.

No top-level findings curated for this source.

PMID:20466812

MicroRNA-140 plays dual roles in both cartilage development and homeostasis.

No top-level findings curated for this source.

PMID:32745689

MicroRNAs in cartilage development and dysplasia.

No top-level findings curated for this source.

PMID:41242538

Transcriptomic profiling confirms microRNA-140 is more functional in joint development than in disease.

No top-level findings curated for this source.

PMID:28426188

Trichorhinophalangeal Syndrome.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 21 citations 2026-09-03T16:17:37.920833

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Spondyloepiphyseal Dysplasia, Nishimura Type (MIR140-related skeletal dysplasia)
MONDO ID: MONDO:0032835 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Spondyloepiphyseal Dysplasia, Nishimura Type (MIR140-related skeletal dysplasia) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Spondyloepiphyseal Dysplasia, Nishimura Type (MIR140-Related Skeletal Dysplasia)

Executive summary and evidence limits

Spondyloepiphyseal dysplasia, Nishimura type is an ultra-rare, autosomal-dominant skeletal dysplasia caused by a neomorphic seed-region variant in the cartilage-enriched microRNA gene MIR140. The defining evidence remains the 2019 Nature Medicine report of only three affected people from two unrelated families. Consequently, phenotype frequencies, penetrance, prevalence, prognosis, and treatment effects cannot yet be estimated reliably. No additional substantive human cohort or disease-specific clinical trial was identified in the 2023–2024 literature searched for this report. The most important recent development is instead a 2023 preclinical metabolic model linking mutant MIR140 to reduced HIF1A/glycolysis, reduced acetyl-CoA and histone acetylation, and possible FGFR3 upregulation in resting-zone chondrocytes. That downstream chain remains partly inferential. (grigelioniene2019gainoffunctionmutationofa pages 1-3, kobayashi2023reducedglycolysislinks pages 26-30, kobayashi2023reducedglycolysislinks pages 1-5)

The compact evidence summary below should be interpreted in light of that very small human denominator.

Field	Key fact	Evidence / uncertainty
Disease identity	Spondyloepiphyseal dysplasia, Nishimura type; also SED, MIR140 type Nishimura or MIR140-related skeletal dysplasia	Ultra-rare, monoallelic Mendelian skeletal dysplasia first delineated in 2019. (grigelioniene2019gainoffunctionmutationof pages 1-3, grigelioniene2019gainoffunctionmutationof pages 6-7)
Identifiers	OMIM 618618; Orphanet 163649; MONDO:0032835	Orphanet identifier is supported by Open Targets; OMIM and MONDO identifiers were user-supplied and were not independently verified with the available tools. (OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)
Causal gene / variant	MIR140 (microRNA 140; Ensembl ENSG00000208017); heterozygous NR_029681.1:n.24A>G, equivalent to chr16:g.69967007A>G (hg19)	The substitution affects the miR-140-5p seed region. Only this recurrent disease-causing variant was established in the retrieved human literature. (grigelioniene2019gainoffunctionmutationof pages 3-4, OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)
Inheritance	Autosomal dominant / monoallelic; de novo in two probands and transmitted from an affected mother to her son	Germline variant with vertical segregation in one family; recurrence risk is 50% for an affected heterozygote, while parental germline mosaicism after an apparently de novo event remains theoretically possible but unquantified. (grigelioniene2019gainoffunctionmutationofa pages 1-3, grigelioniene2019gainoffunctionmutationofa pages 6-7)
Known human evidence	3 affected individuals from 2 unrelated families in the foundational report; PMID 30804514	No substantive additional human cohort was identified through the 2023–2024 literature search, so frequencies and penetrance estimates remain highly uncertain. (grigelioniene2019gainoffunctionmutationofa pages 1-3, OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)
Core phenotype	Disproportionate short stature, short limbs, small hands and feet, severe brachydactyly with cone-shaped phalangeal epiphyses, midface hypoplasia/small nose, delayed hip and knee epiphyseal ossification, small epiphyses, mild platyspondyly/spondylar dysplasia, and scaphocephaly	Adult findings included premature spondylosis and degenerative joint disease; respiratory infections, prolonged cough, stridor, and suspected laryngeal-cartilage laxity/narrowing occurred in two related patients. Intelligence, hearing, vision, dentition, routine blood tests, and age-adjusted bone density were reported as normal where assessed. (grigelioniene2019gainoffunctionmutationofa pages 1-3, grigelioniene2019gainoffunctionmutationof pages 6-7, grigelioniene2019gainoffunctionmutationof pages 3-4)
Mechanism	Neomorphic miRNA seed mutation causes loss of normal targeting plus gain of novel targeting: wild-type miR-140-5p targets are derepressed, mutant-seed targets are repressed, and mutant miR-140-5p competes with YBX1 at overlapping RNA sites	Demonstrated in chondrocytes and a corresponding knock-in mouse. A newer preclinical model proposes a downstream HIF1A↓ → glycolysis↓ → citrate/acetyl-CoA↓ → histone acetylation↓ → FGFR3↑ branch, but direct MIR140-to-FGFR3 epigenetic causality remains inferred. (grigelioniene2019gainoffunctionmutationof pages 1-3, kobayashi2023reducedglycolysislinks pages 26-30, kobayashi2023reducedglycolysislinks pages 1-5)
Diagnosis	Recognition of the characteristic spondyloepiphyseal/brachydactyly pattern followed by sequencing that adequately covers noncoding MIR140; confirm the variant by an orthogonal method and test parents	WES may miss or inadequately prioritize a microRNA locus; WGS enabled discovery after coding-exome analysis was unrevealing. Differentiate from acrodysostosis, which commonly has advanced carpal ossification, endocrine abnormalities, and PDE4D or PRKAR1A variants. No standardized disease-specific criteria or validated biochemical biomarker exists. (grigelioniene2019gainoffunctionmutationof pages 6-7, grigelioniene2019gainoffunctionmutationofa pages 6-7)
Management / trials	No disease-modifying drug, gene/RNA therapy, approved targeted treatment, or disease-specific interventional trial was identified	Care is supportive and individualized: orthopedic and spine surveillance, joint/pain management, physical and occupational therapy, airway/ENT evaluation when symptomatic, and genetic counseling. These measures are extrapolated from skeletal-dysplasia practice rather than tested specifically in MIR140 disease.
Epidemiology	Prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, and geographic distribution are unknown	Only three molecularly confirmed individuals in two families were documented in the retrieved primary human evidence; no founder effect is known. (grigelioniene2019gainoffunctionmutationofa pages 1-3)
Models	CRISPR Mir140 seed knock-in mouse, Mir140-null mouse, primary mouse chondrocytes, reporter/transcriptomic systems, and zebrafish functional assays	Seed knock-in mice reproduce delayed ossification, reduced Col10a1, widened growth plates, expanded resting zones, reduced epiphyseal mineralization, and mildly flat vertebrae; null mice show distinct loss-of-function biology involving DNPEP/BMP and PTHrP–HDAC4–MEF2C/p38 pathways. No naturally occurring veterinary counterpart was identified. (grigelioniene2019gainoffunctionmutationof pages 3-4, papaioannou2015microrna‐140providesrobustness pages 19-22, nakamura2011chondrocytespecificmicrorna140regulates pages 1-2, nakamura2011chondrocytespecificmicrorna140regulates pages 9-10)

Table: Compact evidence summary of the disease identity, defining MIR140 variant, clinical spectrum, mechanism, diagnosis, management, epidemiology, and experimental models. It highlights where conclusions rest on only three reported human cases or on preclinical evidence.

1. Disease information

Definition and nomenclature

The disorder is a congenital growth-plate disease affecting endochondral ossification, vertebral bodies, epiphyses, and short tubular bones. Preferred and alternative names include:

Spondyloepiphyseal dysplasia, Nishimura type
Spondyloepiphyseal dysplasia, MIR140 type
SED MIR140 type Nishimura
MIR140-related skeletal dysplasia

The foundational authors proposed the Nishimura eponym after identifying the same MIR140 variant in two unrelated families. (grigelioniene2019gainoffunctionmutationof pages 6-7, grigelioniene2019gainoffunctionmutationofa pages 6-7)

Identifiers

OMIM phenotype: 618618. Some secondary snippets incorrectly associate 611894 with this entity; 618618 is the identifier consistently attached to SED MIR140 type in the retrieved disease reviews.
Orphanet: ORPHA:163649, independently represented in Open Targets.
MONDO: MONDO:0032835, supplied in the request but not independently resolved by the available tools.
Causal-gene identifiers: MIR140; Ensembl ENSG00000208017; approved name “microRNA 140.” (OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)
ICD-10/ICD-11 and MeSH: no disease-specific code or descriptor was found. It would ordinarily be represented under a broader osteochondrodysplasia/spondyloepiphyseal-dysplasia category.

The clinical information is individual-patient evidence from three published cases; identifiers and gene associations are aggregated disease-level resources derived largely from that report and animal data. Open Targets identifies MIR140 as the sole associated target and gives an aggregate association score of 0.385, drawing on EVA, Gene2Phenotype, IMPC, ClinGen, and the primary publication. (OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)

2. Etiology, risk, protection, and environment

Primary cause

The established cause is a germline heterozygous MIR140 seed-region substitution, NR_029681.1:n.24A>G, corresponding to chr16:g.69967007A>G (hg19). It changes the first nucleotide of the mature miR-140-5p seed and creates an altered target-recognition repertoire. The lesion is not a conventional protein missense variant: Sequence Ontology class mature_miRNA_variant, SO:0001620 is appropriate. (grigelioniene2019gainoffunctionmutationof pages 3-4, OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)

The variant arose de novo in the two independent probands and was transmitted from an affected mother to her son in one family. This establishes monoallelic autosomal-dominant causation. No second pathogenic MIR140 allele or susceptibility locus was established in the retrieved human literature. (grigelioniene2019gainoffunctionmutationofa pages 1-3, grigelioniene2019gainoffunctionmutationofa pages 6-7)

Risk and protective factors

Genetic risk: carrying the pathogenic seed variant is the only demonstrated risk factor. An affected heterozygote has a theoretical 50% transmission probability per pregnancy.
Modifiers: no human modifier gene is established. Experimental genetic interaction with Pthrp and Hdac4, but not clearly with Ihh, has been demonstrated in Mir140-null mice; this is pathway evidence, not a validated human modifier association. (papaioannou2015microrna‐140providesrobustness pages 9-12)
Protective variants: none reported.
Environmental, lifestyle, occupational, dietary, toxic, or infectious causes: none supported. This is a congenital Mendelian disorder, not an acquired dysplasia.
Gene–environment interaction: none demonstrated. Mechanical loading, aging, and body weight could plausibly influence secondary joint degeneration, but this has not been studied in MIR140 patients.

3. Phenotypes

The denominator is three, so statements such as “all” or “two of three” describe the original case series rather than stable population frequencies.

Clinical domain	Reported characteristics and course	Suggested ontology terms
Growth	Congenital/developmental disproportionate short stature with short limbs; severity appears compatible with survival into adulthood, but standardized height data were not available in the extracted evidence	Short stature HP:0004322; disproportionate short stature HP:0003498; micromelia HP:0002983
Hands and feet	Small hands and feet, severe brachydactyly, and cone-shaped phalangeal epiphyses	Brachydactyly HP:0001156; small hand HP:0200055; cone-shaped epiphyses HP:0010579
Spine	Mild spondylar dysplasia/platyspondyly during development; premature spondylosis in adulthood	Platyspondyly HP:0000926; spondylosis
Epiphyses/joints	Delayed hip and knee epiphyseal ossification, small epiphyses, epiphyseal dysplasia; premature degenerative joint disease in adults	Delayed epiphyseal ossification; epiphyseal dysplasia HP:0002656; osteoarthritis HP:0002758
Craniofacial	Midface hypoplasia, small/short nose, and scaphocephaly	Midface retrusion HP:0011800; scaphocephaly HP:0030799
Respiratory/airway	Recurrent respiratory infections, prolonged cough, inspiratory stridor, and suspected narrow/floppy laryngeal cartilage in the affected mother and son	Recurrent respiratory infections HP:0002205; stridor HP:0010307; laryngomalacia HP:0001601, if clinically confirmed
Preserved findings	Intelligence, dentition, hearing, vision, routine blood tests, and endocrine evaluation were reported normal where assessed; age-adjusted bone density was normal in the 43-year-old woman	These are useful negative phenotypes, not defining HPO disease features

These manifestations and negative findings derive from the foundational human report. Adult findings show that the skeletal dysplasia is lifelong and that joint/spine morbidity may progress even after linear growth ends. (grigelioniene2019gainoffunctionmutationofa pages 1-3, grigelioniene2019gainoffunctionmutationof pages 1-3, grigelioniene2019gainoffunctionmutationof pages 6-7)

Quality of life: no EQ-5D, SF-36, PROMIS, pain score, mobility scale, or formal patient-reported outcome was published. Short stature, hand/foot disproportion, degenerative joint disease, spondylosis, and airway symptoms are likely to affect mobility, pain, activities of daily living, and respiratory well-being, but disease-specific effect sizes are unavailable.

4. Genetic and molecular information

Gene and variant interpretation

MIR140 encodes miR-140-5p and miR-140-3p rather than a protein. It is highly enriched in cartilage and lies in a chondrocyte-specific super-enhancer context. The n.24A>G lesion is a seed change with a combined loss of normal function and neomorphic gain of function, not simple haploinsufficiency. The corresponding knock-in phenotype differs from Mir140-null mice, strongly supporting that interpretation. (grigelioniene2019gainoffunctionmutationof pages 1-3, grigelioniene2019gainoffunctionmutationof pages 3-4, nakamura2011chondrocytespecificmicrorna140regulates pages 1-2)

The human evidence and ClinVar/EVA-linked record support pathogenicity, although the Open Targets extraction notes that the EVA assertion had no supplied assertion criteria. A knowledge-base entry should therefore retain the primary functional evidence rather than relying only on an automated ACMG label. (OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)

Variant class: single-nucleotide mature-miRNA seed variant.
Origin: germline; de novo in two probands and inherited in one affected child.
Population frequency: no frequency was supplied by the retrieved sources; the recurrence in two unrelated families and de novo observations imply an extremely rare allele. It should be checked directly in the current gnomAD release before clinical reporting.
Other variants: no additional definitively disease-causing MIR140 variants were found.
Chromosomal abnormalities: none established as causative.
Somatic variation: not relevant to the congenital disorder.
Epigenetics: MIR140 is super-enhancer associated. Reduced histone acetylation is seen in mutant mouse chondrocytes, but no patient-specific DNA-methylation or chromatin signature is validated. (grigelioniene2019gainoffunctionmutationof pages 1-3, kobayashi2023reducedglycolysislinks pages 26-30)

5. Environmental information

No toxin, radiation, pollution, occupation, diet, smoking, alcohol, exercise pattern, or pathogen is known to initiate the disorder. Environmental measures cannot prevent a de novo germline seed mutation. Ordinary orthopedic risk factors may modify secondary osteoarthritis, but no MIR140-specific epidemiologic evidence exists. Infectious disease is not etiologic; recurrent respiratory infections in two patients were manifestations or complications, possibly related to airway cartilage. (grigelioniene2019gainoffunctionmutationofa pages 1-3)

6. Mechanism and pathophysiology

Ordered causal chain

Heterozygous MIR140 n.24A>G alters the first nucleotide of the miR-140-5p seed, which leads to a new RNA-target recognition sequence.
High chondrocyte expression of mutant miR-140-5p leads to simultaneous derepression of normal miR-140-5p targets and repression of novel mutant-seed targets.
Mutant miR-140-5p binding overlaps and competes with YBX1, which leads to unusually strong repression of newly recognized transcripts.
The altered chondrocyte transcriptome leads to impaired growth-plate maturation, reduced COL10A1, widened growth plates, expansion of resting-zone chondrocytes, and delayed epiphyseal mineralization.
These growth-plate abnormalities lead to delayed endochondral ossification, small/dysplastic epiphyses, short limbs, brachydactyly, platyspondyly, and disproportionate short stature.
Abnormal epiphyseal and articular-cartilage development likely leads to premature spondylosis and degenerative joint disease in adulthood (clinically supported, exact molecular bridge inferred).
Branch—metabolic model: mutant Mir140 leads to reduced Hif1a and glycolytic adaptation, which leads to lower cytoplasmic citrate/acetyl-CoA and histone acetylation, which may lead to increased Fgfr3 expression/signaling and resting-zone expansion (mouse evidence; direct MIR140→epigenetic FGFR3 causality remains inferred). (grigelioniene2019gainoffunctionmutationof pages 3-4, kobayashi2023reducedglycolysislinks pages 26-30, kobayashi2023reducedglycolysislinks pages 1-5)

Detailed pathway interpretation

The 2019 study demonstrated abundant mutant miR-140-5p without a gross miRNA-processing defect. Chondrocyte transcriptomics showed widespread loss of repression of wild-type targets and gain of repression at novel, particularly predicted 8-mer, mutant-seed sites. Competition with YBX1, an RNA-binding protein recognizing overlapping motifs, provides a mechanistic explanation for the potency of a newly created miRNA seed that lacks evolutionary coadaptation with its targets. The authors’ abstract states: “the mutation produces both loss-of-function and gain-of-function effects” and describes the report as “the first case of a pathogenic gain-of-function miRNA mutation.” (grigelioniene2019gainoffunctionmutationof pages 1-3, grigelioniene2019gainoffunctionmutationof pages 3-4)

The 2023 preprint broadened this model. Chondrocyte-specific deletion of Ldha/Ldhb reduced glycolysis and reproduced resting-zone expansion; deletion of Acly reduced acetyl-CoA and reproduced the phenotype without generalized energy deficiency. Overlapping transcriptomic changes included Fgfr3 upregulation, and constitutively active FGFR3 expanded the resting zone. The authors’ abstract concludes that reduced glycolysis is linked to acetyl-CoA deficiency, “possibly through epigenetic upregulation of FGFR3 signaling.” “Possibly” is critical: direct increased FGFR3 signaling and direct chromatin deregulation of Fgfr3 were not demonstrated in the extracted evidence. RNA-seq data were deposited as GEO GSE192971. (kobayashi2023reducedglycolysislinks pages 26-30, kobayashi2023reducedglycolysislinks pages 1-5, kobayashi2023reducedglycolysislinks pages 5-8)

Relevant processes and ontology suggestions include:

miRNA-mediated post-transcriptional gene silencing — GO:0035195
regulation of gene expression — GO:0010468
chondrocyte differentiation — GO:0002062
cartilage development — GO:0051216
endochondral ossification — GO:0001958
histone acetylation — GO:0016573
glycolytic process — GO:0006096
BMP signaling — GO:0030509
MAPK cascade — GO:0000165
principal cell: chondrocyte — CL:0000138; resting, proliferative, and hypertrophic growth-plate chondrocyte subtypes should be represented where the target ontology supports them.

Important distinction: Mir140-null mechanisms—DNPEP/BMP attenuation, increased p38-MAPK/MEF2C, and interaction with PTHrP–HDAC4—clarify normal miR-140 biology but are not equivalent to the human seed-mutant mechanism. Null mice have short endochondral bones, craniofacial abnormalities, accelerated hypertrophy, and impaired resting-to-columnar differentiation; heterozygous null mice were reportedly indistinguishable from wild type. (papaioannou2015microrna‐140providesrobustness pages 19-22, nakamura2011chondrocytespecificmicrorna140regulates pages 1-2, nakamura2011chondrocytespecificmicrorna140regulates pages 9-10)

No disease-specific proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, patient-iPSC, organoid, or CRISPR-screen dataset was identified. Lipid synthesis and Ras prenylation showed no overt deficit in the metabolic models, arguing against lipid shortage as the principal downstream mechanism. (kobayashi2023reducedglycolysislinks pages 26-30)

7. Anatomical structures affected

Primary involvement is bilateral/systemic rather than unilateral:

Organs/system: skeleton and joints; possible upper airway cartilage.
Sites: vertebral bodies, long-bone growth plates and epiphyses—especially hip and knee—phalanges, skull, and facial skeleton.
Tissues: hyaline growth-plate cartilage, epiphyseal/articular cartilage, and bone formed by endochondral ossification.
Cells: resting-zone, proliferating/columnar, prehypertrophic, and hypertrophic chondrocytes; osteoblast abnormalities are secondary to disturbed cartilage-template maturation rather than a demonstrated primary osteoblast lesion.
Subcellular structures: nuclear/cytoplasmic miRNA-processing and Argonaute/RISC machinery; target mRNAs and YBX1-containing ribonucleoprotein interactions. No mitochondrial structural defect is established.

Suggested UBERON concepts include cartilage tissue (UBERON:0002418), growth plate cartilage, epiphysis, vertebral body, phalanx, hip joint, knee joint, and laryngeal cartilage. (grigelioniene2019gainoffunctionmutationofa pages 1-3, grigelioniene2019gainoffunctionmutationof pages 3-4)

8. Temporal development

Onset is congenital/developmental, although the exact prenatal ultrasound phenotype is unknown. Delayed secondary ossification and disproportion become evident in childhood. The disease is chronic and lifelong rather than episodic or remitting. Growth-plate abnormalities dominate childhood; premature spondylosis and degenerative joint disease emerge or worsen in adulthood. A 45-year-old affected woman and her affected son demonstrate survival into adulthood and vertical transmission. (grigelioniene2019gainoffunctionmutationof pages 6-7, grigelioniene2019gainoffunctionmutationofa pages 6-7)

There is no validated staging system, progression rate, remission pattern, or critical therapeutic window. Biologically, the period before growth-plate closure is likely the principal window for any future growth-directed intervention, whereas lifelong surveillance addresses joint, spine, and airway complications.

9. Inheritance and population

Inheritance: autosomal dominant, monoallelic.
Penetrance: appears high for the reported variant because all three carriers were affected, but three observations cannot establish complete penetrance.
Expressivity: some variability is evident, especially age-dependent degeneration and respiratory involvement.
Anticipation: not reported and mechanistically unexpected for a single-nucleotide variant.
Mosaicism: no somatic or germline mosaic case reported; low-level parental germline mosaicism remains a standard theoretical consideration after an apparently de novo diagnosis.
Founder effect/consanguinity: none reported; consanguinity is not relevant to the dominant mechanism.
Carrier frequency, incidence, prevalence, sex ratio, ethnicity, and geographic distribution: unknown. The evidence base—three affected individuals in two unrelated families—is too small for rates per 100,000 or demographic inference. (grigelioniene2019gainoffunctionmutationofa pages 1-3)

10. Diagnostics

Clinical and radiographic diagnosis

A diagnostic work-up should begin with history, three-generation pedigree, anthropometry including sitting-height/leg-length proportions, hand and foot examination, and a skeletal survey. Hallmark radiographic findings are delayed hip/knee epiphyseal ossification, small or dysplastic epiphyses, cone-shaped phalangeal epiphyses, severe brachydactyly, and mild platyspondyly. Spine and joint imaging should be symptom directed in adults. Airway endoscopy or dynamic imaging may be considered for stridor, but no disease-specific airway protocol exists. (grigelioniene2019gainoffunctionmutationofa pages 1-3, grigelioniene2019gainoffunctionmutationof pages 3-4)

No diagnostic serum enzyme, metabolite, circulating miRNA, histopathologic criterion, or electrophysiologic biomarker is validated. Routine laboratory and endocrine tests may help exclude mimics but can be normal in MIR140 disease. (grigelioniene2019gainoffunctionmutationof pages 1-3, grigelioniene2019gainoffunctionmutationof pages 6-7)

Genetic testing strategy

Use a skeletal-dysplasia panel that explicitly includes noncoding MIR140, or WGS with analysis of miRNA genes.
If prior WES was negative, review whether MIR140 was captured and interpreted; the original discovery required WGS after coding-exome analysis did not identify a cause.
Confirm a candidate variant by an orthogonal assay and perform parental testing to determine de novo versus inherited status.
Use segregation, population databases, mature-miRNA seed location, and functional literature in classification.

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line tests for the canonical phenotype unless another diagnosis is suspected. RNA-seq, proteomics, metabolomics, and methylation profiling remain research tools rather than validated diagnostics. (grigelioniene2019gainoffunctionmutationofa pages 6-7)

Differential diagnosis

The closest explicitly discussed mimic is acrodysostosis due to PDE4D or PRKAR1A. Both can cause midface hypoplasia and brachydactyly with cone epiphyses. MIR140 disease instead shows delayed epiphyseal maturation/epiphyseal dysplasia, whereas acrodysostosis characteristically has advanced carpal maturation and may include endocrine resistance. The reported MIR140 patients lacked PDE4D/PRKAR1A variants and characteristic endocrine abnormalities. (grigelioniene2019gainoffunctionmutationof pages 6-7, grigelioniene2019gainoffunctionmutationofa pages 6-7)

Other radiographic differentials include COL2A1-related spondyloepiphyseal dysplasia, TRPV4-related dysplasias, ACAN-related short stature/spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, and other brachydactyly–epiphyseal dysplasia syndromes; molecular testing is usually decisive.

There is no newborn population screening. Once a familial variant is known, cascade testing, prenatal diagnosis, and preimplantation genetic testing are technically possible after nondirective genetic counseling.

11. Outcome and prognosis

No survival curve, mortality rate, life-expectancy estimate, disability-adjusted life-year analysis, or validated prognostic biomarker exists. Survival into the fifth decade is documented, and no lethal visceral phenotype was reported. Normal intelligence and absence of a consistent major neurologic, cardiac, renal, or endocrine disorder are relatively favorable findings. (grigelioniene2019gainoffunctionmutationof pages 1-3, grigelioniene2019gainoffunctionmutationof pages 6-7)

Likely major morbidity is orthopedic: short stature, altered biomechanics, premature joint degeneration, spondylosis, pain, and mobility limitation. Respiratory morbidity may occur when laryngeal cartilage is involved. Recovery from the underlying dysplasia is not expected; symptomatic function may improve with rehabilitation or orthopedic treatment. Age, baseline epiphyseal abnormality, mechanical joint burden, and airway involvement are plausible prognostic factors, but none is validated.

12. Treatment and current applications

No approved disease-modifying treatment, genotype-directed drug, RNA therapy, gene therapy, cell therapy, or MIR140-specific surgical outcome series exists. No disease-specific ClinicalTrials.gov interventional study was identified. Broad skeletal-disorder observational studies should not be treated as therapeutic evidence for this disease.

Current real-world care is therefore individualized and multidisciplinary:

pediatric genetics and skeletal-dysplasia expertise;
serial growth, limb-alignment, hip/knee, and spine assessment;
physical therapy, occupational therapy, joint protection, weight optimization, and mobility aids when needed;
standard analgesic and osteoarthritis care, individualized to age and comorbidity;
orthopedic procedures for clinically significant deformity or end-stage joint disease, based on anatomy rather than disease-specific evidence;
ENT/pulmonology evaluation for stridor, recurrent infections, or suspected laryngomalacia;
genetic counseling and psychosocial support.

Suggested NCIt intervention concepts include Genetic Counseling, Physical Therapy, Occupational Therapy, Pain Management, Orthopedic Surgery, and Respiratory Monitoring. No response rate or MIR140-specific adverse-event estimate is available.

Although mutant-miRNA inhibition, seed-selective oligonucleotides, restoration of wild-type target regulation, or modulation of downstream FGFR3 signaling are conceivable precision strategies, none has reached human testing. Because the mutant combines loss and gain of targeting, nonspecific miR-140 replacement or inhibition could worsen one mechanistic branch; target and allele selectivity would be essential. The 2023 FGFR3 observation is hypothesis-generating, not a basis for off-label FGFR inhibition. (kobayashi2023reducedglycolysislinks pages 26-30, kobayashi2023reducedglycolysislinks pages 1-5)

13. Prevention

Primary prevention by lifestyle or vaccination is not applicable. For affected families, reproductive prevention options are genetic counseling, familial-variant testing, prenatal diagnosis, and preimplantation genetic testing. For an apparently de novo case, recurrence risk is low but not zero because parental germline mosaicism cannot be excluded; an affected heterozygote has a 50% transmission risk.

Secondary prevention consists of early molecular diagnosis and surveillance for growth, alignment, spine/joint degeneration, and airway symptoms. Tertiary prevention includes joint protection, rehabilitation, healthy weight, timely orthopedic care, and respiratory management. There is no prophylactic medication, immunization, public-health program, or population carrier-screening recommendation specific to MIR140 disease.

14. Other species and natural disease

No naturally occurring MIR140-associated veterinary disease, breed predisposition, zoonotic transmission, or cross-species infectious risk was identified. Relevant experimental species are:

Mus musculus, NCBI Taxonomy 10090: Mir140-null and seed knock-in models.
Danio rerio, NCBI Taxonomy 7955: miR-140/Dnpep functional developmental assays.
Homo sapiens, NCBI Taxonomy 9606: human disease and cultured-cell evidence.

MIR140 sequence and cartilage enrichment are evolutionarily conserved, supporting comparative validity, but engineered phenotypes must not be labeled natural animal disease. (nakamura2011chondrocytespecificmicrorna140regulates pages 1-2, nakamura2011chondrocytespecificmicrorna140regulates pages 9-10, OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)

15. Model organisms

Seed knock-in mouse—the closest disease model

CRISPR mice carrying the corresponding A-to-G seed substitution show dose-dependent skeletal abnormalities. Heterozygous and homozygous animals exhibit short stature/short nose, delayed ossification, reduced Col10a1, delayed cartilage maturation, reduced epiphyseal mineralization, widened growth plates, expanded resting zones, and mildly flattened vertebral bodies. Their phenotype differs from Mir140-null mice, reproducing the human neomorphic mechanism rather than simple deficiency. Limitations include species-specific growth-plate biology, greater severity in homozygotes—whereas known patients are heterozygous—and incomplete modeling of adult joint, airway, and quality-of-life outcomes. (grigelioniene2019gainoffunctionmutationof pages 3-4, grigelioniene2019gainoffunctionmutationofa pages 3-4, kobayashi2023reducedglycolysislinks pages 5-8)

Mir140-null mouse

Null mice have growth retardation, shortened endochondral bones, craniofacial deformation, fewer columnar proliferating chondrocytes, accelerated hypertrophic differentiation, and impaired resting-to-columnar transition. Mechanistic experiments implicate DNPEP-mediated attenuation of BMP signaling and a PTHrP–HDAC4–MEF2C/p38-MAPK regulatory axis. PTHrP-pathway activation partially rescued skeletal defects, while reduced Pthrp or Hdac4 dosage worsened them. These models define physiological miR-140 functions but only partially model the loss-of-normal-targeting branch of the human mutation. (papaioannou2015microrna‐140providesrobustness pages 19-22, papaioannou2015microrna‐140providesrobustness pages 9-12, nakamura2011chondrocytespecificmicrorna140regulates pages 1-2)

Cellular, zebrafish, and omics systems

Primary mouse rib chondrocytes, reporter assays, small-RNA sequencing, and transcriptomics demonstrated altered wild-type and mutant target repression and YBX1 competition. Zebrafish assays showed that Dnpep transcripts could rescue a miR-140-induced palatal defect, supporting direct miR-140–Dnpep regulation. The 2023 Ldh/Acly/Fgfr3 mouse and chondrocyte systems probe the metabolic/epigenetic branch; they are valuable for target validation but are not themselves MIR140-specific therapies. (grigelioniene2019gainoffunctionmutationof pages 1-3, kobayashi2023reducedglycolysislinks pages 1-5, nakamura2011chondrocytespecificmicrorna140regulates pages 9-10)

Recent research status and expert assessment

The 2024 review literature recognizes MIR140 skeletal dysplasia as a paradigmatic rare disease caused by altered microRNA target recognition, but it does not add a new clinical cohort. The field’s authoritative interpretation is that this is not merely miR-140 deficiency: the disease arises from simultaneous loss of ancestral targeting and acquisition of a novel, YBX1-competing target network. (grigelioniene2019gainoffunctionmutationof pages 1-3, goel2024micrornaandrare pages 14-15)

The strongest unmet needs are independent case ascertainment, standardized longitudinal phenotyping, current population-frequency confirmation, patient-derived chondrocytes or iPSCs, direct mapping of mutant targets responsible for human disease, validation of the proposed HIF1A–acetyl-CoA–FGFR3 branch, and development of allele-selective RNA therapeutics. Until those gaps are addressed, clinical decisions should rely on molecular confirmation, radiographic pattern recognition, multidisciplinary supportive care, and transparent acknowledgment that most mechanistic depth comes from engineered animals and cells rather than treatment studies.

Key publications and URLs

Grigelioniene G, et al. “Gain-of-function mutation of microRNA-140 in human skeletal dysplasia.” Nature Medicine. Published online 25 February 2019; 25:583–590. PMID: 30804514. DOI/URL: https://doi.org/10.1038/s41591-019-0353-2. This is the defining primary human, mouse, and mechanistic study. (grigelioniene2019gainoffunctionmutationof pages 1-3, OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140)
Kobayashi T, Young C, Zhou W, Rhee EP. “Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate.” bioRxiv. January 2023. DOI/URL: https://doi.org/10.1101/2023.01.18.524550. Preclinical preprint; GEO GSE192971. (kobayashi2023reducedglycolysislinks pages 1-5, kobayashi2023reducedglycolysislinks pages 5-8)
Nakamura Y, et al. “Chondrocyte-Specific MicroRNA-140 Regulates Endochondral Bone Development and Targets Dnpep To Modulate Bone Morphogenetic Protein Signaling.” Molecular and Cellular Biology. 2011;31:3019–3028. DOI/URL: https://doi.org/10.1128/MCB.05178-11. Primary mouse/chondrocyte study. (nakamura2011chondrocytespecificmicrorna140regulates pages 1-2, nakamura2011chondrocytespecificmicrorna140regulates pages 9-10)
Papaioannou G, et al. “MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway.” Journal of Bone and Mineral Research. June 2015;30:1044–1052. DOI/URL: https://doi.org/10.1002/jbmr.2438. Primary mouse/chondrocyte study. (papaioannou2015microrna‐140providesrobustness pages 19-22, papaioannou2015microrna‐140providesrobustness pages 9-12)
Goel H, Goel A. “MicroRNA and Rare Human Diseases.” Genes. September 2024;15:1243. DOI/URL: https://doi.org/10.3390/genes15101243. Recent review; useful context but not new patient evidence. (goel2024micrornaandrare pages 14-15)

References

(grigelioniene2019gainoffunctionmutationofa pages 1-3): G. Grigelioniene, Hiroshi I. Suzuki, F. Taylan, Fatemeh Mirzamohammadi, Z. Borochowitz, U. Ayturk, S. Tzur, E. Horemuzova, A. Lindstrand, M. Weis, Gintautas Grigelionis, A. Hammarsjö, E. Marsk, A. Nordgren, M. Nordenskjöld, D. Eyre, M. Warman, G. Nishimura, P. Sharp, and Tatsuya Kobayashi. Gain-of-function mutation of microrna-140 in human skeletal dysplasia. Sep 2019. URL: https://doi.org/10.1530/ey.16.5.6, doi:10.1530/ey.16.5.6. This article has 89 citations.
(kobayashi2023reducedglycolysislinks pages 26-30): Tatsuya Kobayashi, Cameron Young, Wen Zhou, and Eugene P. Rhee. Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate. bioRxiv, Jan 2023. URL: https://doi.org/10.1101/2023.01.18.524550, doi:10.1101/2023.01.18.524550. This article has 4 citations.
(kobayashi2023reducedglycolysislinks pages 1-5): Tatsuya Kobayashi, Cameron Young, Wen Zhou, and Eugene P. Rhee. Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate. bioRxiv, Jan 2023. URL: https://doi.org/10.1101/2023.01.18.524550, doi:10.1101/2023.01.18.524550. This article has 4 citations.
(grigelioniene2019gainoffunctionmutationof pages 1-3): Giedre Grigelioniene, Hiroshi I. Suzuki, Fulya Taylan, Fatemeh Mirzamohammadi, Zvi U. Borochowitz, Ugur M. Ayturk, Shay Tzur, Eva Horemuzova, Anna Lindstrand, Mary Ann Weis, Gintautas Grigelionis, Anna Hammarsjö, Elin Marsk, Ann Nordgren, Magnus Nordenskjöld, David R. Eyre, Matthew L. Warman, Gen Nishimura, Phillip A. Sharp, and Tatsuya Kobayashi. Gain-of-function mutation of microrna-140 in human skeletal dysplasia. Feb 2019. URL: https://doi.org/10.1038/s41591-019-0353-2, doi:10.1038/s41591-019-0353-2. This article has 112 citations and is from a highest quality peer-reviewed journal.
(grigelioniene2019gainoffunctionmutationof pages 6-7): Giedre Grigelioniene, Hiroshi I. Suzuki, Fulya Taylan, Fatemeh Mirzamohammadi, Zvi U. Borochowitz, Ugur M. Ayturk, Shay Tzur, Eva Horemuzova, Anna Lindstrand, Mary Ann Weis, Gintautas Grigelionis, Anna Hammarsjö, Elin Marsk, Ann Nordgren, Magnus Nordenskjöld, David R. Eyre, Matthew L. Warman, Gen Nishimura, Phillip A. Sharp, and Tatsuya Kobayashi. Gain-of-function mutation of microrna-140 in human skeletal dysplasia. Feb 2019. URL: https://doi.org/10.1038/s41591-019-0353-2, doi:10.1038/s41591-019-0353-2. This article has 112 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: Spondyloepiphyseal dysplasia Nishimura type-MIR140): Open Targets Query (Spondyloepiphyseal dysplasia Nishimura type-MIR140, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(grigelioniene2019gainoffunctionmutationof pages 3-4): Giedre Grigelioniene, Hiroshi I. Suzuki, Fulya Taylan, Fatemeh Mirzamohammadi, Zvi U. Borochowitz, Ugur M. Ayturk, Shay Tzur, Eva Horemuzova, Anna Lindstrand, Mary Ann Weis, Gintautas Grigelionis, Anna Hammarsjö, Elin Marsk, Ann Nordgren, Magnus Nordenskjöld, David R. Eyre, Matthew L. Warman, Gen Nishimura, Phillip A. Sharp, and Tatsuya Kobayashi. Gain-of-function mutation of microrna-140 in human skeletal dysplasia. Feb 2019. URL: https://doi.org/10.1038/s41591-019-0353-2, doi:10.1038/s41591-019-0353-2. This article has 112 citations and is from a highest quality peer-reviewed journal.
(grigelioniene2019gainoffunctionmutationofa pages 6-7): G. Grigelioniene, Hiroshi I. Suzuki, F. Taylan, Fatemeh Mirzamohammadi, Z. Borochowitz, U. Ayturk, S. Tzur, E. Horemuzova, A. Lindstrand, M. Weis, Gintautas Grigelionis, A. Hammarsjö, E. Marsk, A. Nordgren, M. Nordenskjöld, D. Eyre, M. Warman, G. Nishimura, P. Sharp, and Tatsuya Kobayashi. Gain-of-function mutation of microrna-140 in human skeletal dysplasia. Sep 2019. URL: https://doi.org/10.1530/ey.16.5.6, doi:10.1530/ey.16.5.6. This article has 89 citations.
(papaioannou2015microrna‐140providesrobustness pages 19-22): Garyfallia Papaioannou, Fatemeh Mirzamohammadi, Thomas S Lisse, Shigeki Nishimori, Marc N Wein, and Tatsuya Kobayashi. Microrna‐140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the pthrp‐hdac4 pathway. Journal of Bone and Mineral Research, 30:1044-1052, Jun 2015. URL: https://doi.org/10.1002/jbmr.2438, doi:10.1002/jbmr.2438. This article has 67 citations and is from a highest quality peer-reviewed journal.
(nakamura2011chondrocytespecificmicrorna140regulates pages 1-2): Yukio Nakamura, Jennifer B. Inloes, Takenobu Katagiri, and Tatsuya Kobayashi. Chondrocyte-specific microrna-140 regulates endochondral bone development and targets dnpep to modulate bone morphogenetic protein signaling. Jul 2011. URL: https://doi.org/10.1128/mcb.05178-11, doi:10.1128/mcb.05178-11. This article has 236 citations and is from a domain leading peer-reviewed journal.
(nakamura2011chondrocytespecificmicrorna140regulates pages 9-10): Yukio Nakamura, Jennifer B. Inloes, Takenobu Katagiri, and Tatsuya Kobayashi. Chondrocyte-specific microrna-140 regulates endochondral bone development and targets dnpep to modulate bone morphogenetic protein signaling. Jul 2011. URL: https://doi.org/10.1128/mcb.05178-11, doi:10.1128/mcb.05178-11. This article has 236 citations and is from a domain leading peer-reviewed journal.
(papaioannou2015microrna‐140providesrobustness pages 9-12): Garyfallia Papaioannou, Fatemeh Mirzamohammadi, Thomas S Lisse, Shigeki Nishimori, Marc N Wein, and Tatsuya Kobayashi. Microrna‐140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the pthrp‐hdac4 pathway. Journal of Bone and Mineral Research, 30:1044-1052, Jun 2015. URL: https://doi.org/10.1002/jbmr.2438, doi:10.1002/jbmr.2438. This article has 67 citations and is from a highest quality peer-reviewed journal.
(kobayashi2023reducedglycolysislinks pages 5-8): Tatsuya Kobayashi, Cameron Young, Wen Zhou, and Eugene P. Rhee. Reduced glycolysis links resting zone chondrocyte proliferation in the growth plate. bioRxiv, Jan 2023. URL: https://doi.org/10.1101/2023.01.18.524550, doi:10.1101/2023.01.18.524550. This article has 4 citations.
(grigelioniene2019gainoffunctionmutationofa pages 3-4): G. Grigelioniene, Hiroshi I. Suzuki, F. Taylan, Fatemeh Mirzamohammadi, Z. Borochowitz, U. Ayturk, S. Tzur, E. Horemuzova, A. Lindstrand, M. Weis, Gintautas Grigelionis, A. Hammarsjö, E. Marsk, A. Nordgren, M. Nordenskjöld, D. Eyre, M. Warman, G. Nishimura, P. Sharp, and Tatsuya Kobayashi. Gain-of-function mutation of microrna-140 in human skeletal dysplasia. Sep 2019. URL: https://doi.org/10.1530/ey.16.5.6, doi:10.1530/ey.16.5.6. This article has 89 citations.
(goel2024micrornaandrare pages 14-15): Himanshu Goel and Amy Goel. Microrna and rare human diseases. Genes, 15:1243, Sep 2024. URL: https://doi.org/10.3390/genes15101243, doi:10.3390/genes15101243. This article has 20 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
On topic	3
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

DOI:10.1002/jbmr.2438 (7 mentions) - MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway
shared terms: none

Weighed against this report's own most characteristic terms: disease, human, gene, clinical, dysplasia, genetic, type, affected, model, mir140, variant, phenotype, target, primary, joint, spondyloepiphyseal, skeletal, nishimura, abnormalitie, seed.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	28
Resolved	26
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0032835 (3 mentions) - the report calls it "if available"; MONDO calls it spondyloepiphyseal dysplasia, nishimura type

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0016573 (obsolete histone acetylation) (1 mention)

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Diagnosis

Progression

Prevalence

Differential Diagnoses

Related Datasets

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Spondyloepiphyseal Dysplasia, Nishimura Type (MIR140-Related Skeletal Dysplasia)

Executive summary and evidence limits

1. Disease information

Definition and nomenclature

Identifiers

2. Etiology, risk, protection, and environment

Primary cause

Risk and protective factors

3. Phenotypes

4. Genetic and molecular information

Gene and variant interpretation

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Detailed pathway interpretation

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and radiographic diagnosis

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

14. Other species and natural disease

15. Model organisms

Seed knock-in mouse—the closest disease model

Mir140-null mouse

Cellular, zebrafish, and omics systems

Recent research status and expert assessment

Key publications and URLs

Artifacts

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Obsolete terms

Prefixes with no resolver