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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic inactivating SCUBE3 variants; reported families are frequently consanguineous.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:37237303 SUPPORT Human Clinical

"Eight bi-allelic inactivating variants in SCUBE3 were first discovered and characterized by our research in 18 affected people from nine independent families who shared the same phenotype"

Biallelic variants across nine independent families establish recessive inheritance.

PMID:33308444 SUPPORT Human Clinical

"Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder."

The primary source for the recessive, inactivating-variant architecture.

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Discussions and Knowledge Gaps

6

Why is the Scube3 null mouse viable, fertile and grossly normal at birth when biallelic SCUBE3 loss in humans produces prenatal growth restriction and a recognizable multisystem syndrome?

HUMAN MODEL MISMATCH OPEN scube3_mouse_null_milder_than_human

Attached to

pathophysiology#Impaired BMP-Mediated Chondrogenesis and Osteogenesis animal_models#Scube3 knockout mouse

This is a mismatch in severity rather than in kind: the knockout does reproduce the craniofacial, dental and endochondral domains, so the model is informative, but it does not reproduce how much they cost the organism. The standing explanation is redundancy with the other SCUBE family members, and the zebrafish work makes that concrete - single scube mutants are mild while triple mutants approach a complete Hedgehog loss-of-function phenotype. That explanation has a consequence for interpreting this disease, which is why it is worth recording rather than filing as a caveat: if compensation by SCUBE1 and SCUBE2 sets how severe a given individual is, then the variable expressivity in patients may be modifier-driven rather than allele-driven, and no study has tested that. Note also that the zebrafish result is Hedgehog, not BMP, and mouse Scube3 does not affect Hedgehog - so the redundancy argument is being carried across species and across pathways, and it has not been shown for BMP in mammals.

Show evidence (4 references)

PMID:37237303 SUPPORT Model Organism

"mice that are homozygous for the tm1(KOPM)Vlcg allele (Scube3−/−) are born at expected Mendelian ratios, show no overt embryonic phenotypes, and are both viable and fertile"

The half of the mismatch that concerns the mouse: the null is viable, fertile and grossly normal at birth.

PMID:37237303 SUPPORT Model Organism

"mouse Scube3 does not appear to affect the HH pathway, unlike zebrafish scube3"

Sources this discussion's own caveat against itself: the redundancy argument is carried from a Hedgehog result in zebrafish to a BMP claim in mammals, and this sentence is why that step is not safe.

PMID:40912446 SUPPORT INDIRECT Other

"Individual functional characterisation has proved challenging because of overlapping expression patterns and compensatory mechanisms that likely obscure specific roles."

States the compensation problem the redundancy explanation rests on. Graded OTHER because the sentence describes the difficulty of the research rather than reporting a zebrafish result, and INDIRECT because it is the premise of the argument rather than a demonstration of it.

+ 1 more reference

Is there any SCUBE3-specific management, and does recombinant growth hormone help these patients?

KNOWLEDGE GAP OPEN scube3_no_disease_specific_management_evidence

Attached to

treatments#

The treatments section is empty on purpose. A PubMed search for SCUBE3 with growth hormone, treatment, or management returns no interventional study, no case series reporting a growth response, and no management guideline, and there is no GeneReviews chapter for this gene. Management is presumed symptomatic - orthopaedic care for the spine, dental care, growth monitoring - but nothing supports a treatment entry with a citation, so none is curated. The question is not idle: this disorder is reached through short stature clinics, where recombinant growth hormone is the default question, and the disease mechanism gives a reason to expect it to disappoint. The lesion is in the growth plate's response to BMP rather than in the GH-IGF-I axis, and the cohort that found SCUBE3 explicitly sorted it out of the GH-IGF-I subgroup. That is a mechanistic prediction, not a finding, and it is recorded here so it is not mistaken for one.

Show evidence (1 reference)

PMID:38838658 SUPPORT Human Clinical

"In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions."

Places SCUBE3 outside the GH-IGF-I axis group in the only cohort that sorted short-stature genes by that axis, which is the basis for the expectation stated above.

Should the majority-frequency phenotypes in the HPO annotation set for OMIM:619184 be curated, and from what citable source?

CURATION TODO OPEN scube3_phenotype_frequencies_not_quotable

Attached to

phenotypes#

This entry curates ten phenotypes, and the four skeletal ones added most recently come from a single case report's radiology. That is a strange shape, and the reason is worth recording rather than leaving to be rediscovered. The deep-research reports carry a fuller list with HPO identifiers and denominators - brachydactyly and dental crowding at roughly 80% (12/15), pointed chin ~85%, short palm ~80%, short long bone ~55%, enamel hypoplasia ~27%, and recurrent conductive hearing loss - all of which are more frequent than what is curated here. None was added, because the numbers come from HPO disease annotations rather than from a sentence in a reference this repository can cache, and the abstract of the discovery cohort (PMID:33308444) gives only the four domain headings. So the choice was between verifiable content and coverage, and this entry took verifiability. Closing this needs the full text of PMID:33308444, or the HPO annotation file treated as a citable source in its own right - which would also settle the cardiac and rib-number questions recorded separately here.

The absence of these phenotypes is a sourcing limit, not a claim that patients do not have them.

Does the discovery cohort report atrial septal defect, and if so should this entry carry a cardiac phenotype?

CURATION TODO OPEN scube3_cardiac_clause_unresolved

Attached to

disease#SCUBE3-Related Short Stature Syndrome

The bound disease label ends "with or without cardiac anomalies", and this entry curates no cardiac phenotype. The reason is a cache limit, not a finding. The discovery cohort's abstract (PMID:33308444) lists reduced growth, skeletal features, craniofacial appearance and dental anomalies and no cardiac involvement, and its full text is not retrievable into references_cache, so nothing quotable exists either way. Two independent deep-research runs against different providers both report atrial septal defect in two of the cohort and patent foramen ovale in two, attributing it to HPO annotations on OMIM:619184; agreement between them is weak evidence because both are reading the same annotation set rather than the paper. Resolving this needs the full text of PMID:33308444 or the HPO annotation file cited as a source in its own right. Until then the phenotype is absent from this entry, and its absence should not be read as a negative finding.

Do not resolve this from a deep-research report. The claim needs a source whose exact sentence can be quoted and cached.

Does loss of the SCUBE3 TGF-beta arm contribute to the human skeletal phenotype, or is the disease entirely a BMP deficit?

OPEN QUESTION OPEN scube3_tgf_beta_arm_contribution_unknown

Attached to

pathophysiology#Loss of SCUBE3 BMP Co-Receptor Function

This entry models the disorder as a BMP co-receptor loss, which is what the disease literature demonstrates. SCUBE3 also has a separate, well characterized TGF-beta activity: its C-terminal CUB domain binds TGF-beta type II receptor directly and induces SMAD2/3 phosphorylation, so SCUBE3 is a ligand there rather than a co-receptor, and the downstream SMAD branch is a different one. That work was done in lung cancer cells, which is why it is a question here rather than a pathophysiology node - the same molecular interaction in a growth plate would be a different claim. Two observations keep it open. Recombinant SCUBE3 raises both BMP2 and TGF-beta in human bone-marrow mesenchymal stem cells and restores osteogenesis through SMAD phosphorylation, without the two branches being separated; and the SCUBE3-overexpressing transgenic mouse develops cardiac hypertrophy through TGF-beta1, showing the arm is active in vivo in a mammal. Nobody has asked which branch the skeletal phenotype needs.

Show evidence (2 references)

PMID:21441952 SUPPORT INDIRECT In Vitro

"bound to transforming growth factor-β (TGF-β) type II receptor through the C-terminal CUB domain, activated TGF-β signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation"

Establishes the TGF-beta arm as a real biochemical activity of SCUBE3. Graded INDIRECT because it was shown in lung cancer cells: it supports the existence of the arm this question is about, not its operation in the growth plate.

PMID:39250278 SUPPORT INDIRECT In Vitro

"treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation"

Both pathways move together in a skeletal cell type, and the study does not separate them. That is what leaves the question open rather than answering it.

Does SCUBE3 loss disturb somitogenesis, or is the reduced rib number a coincidental finding in one patient?

OPEN QUESTION OPEN scube3_rib_number_not_explained_by_growth_plate_defect

Attached to

phenotypes#11 pairs of ribs pathophysiology#Impaired BMP-Mediated Chondrogenesis and Osteogenesis

Every other skeletal feature in this entry follows from defective endochondral bone growth, which acts on bones that already exist. Rib number does not: it is fixed by axial patterning during somitogenesis, well before the growth plate forms, so the curated mechanism does not reach it. Two readings are open. Either SCUBE3 has an earlier patterning role that nobody has looked for - BMP signalling does act in somite patterning, and mouse Scube3 is expressed in the cartilaginous condensations of ribs and vertebrae - or the finding is incidental. The second reading is the weaker one: a deep-research report puts eleven rib pairs at roughly 31% (4/13) of the cohort, which is recurrent rather than incidental, though that figure comes from HPO annotations and is not quotable in this entry. Settling it needs published rib counts across the reported cohort. Eleven rib pairs is also reported in SSFSC1, the BMP2-related disorder that shares this disease's naming series, which would fit a shared BMP-pathway patterning effect if it holds up.

Show evidence (2 references)

PMID:40331102 SUPPORT Human Clinical

"skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"

The single report of the finding this question is about.

PMID:40331102 SUPPORT Human Clinical

"SCUBE3 protein exhibits significant expression in various tissues, including primary osteoblasts, long bones, and the cartilage of the axial skeleton throughout development, while also playing a regulatory role in the FGF, Hedgehog, and TGF-β signaling pathways."

Axial-skeleton cartilage expression throughout development is what makes an earlier patterning role worth asking about rather than dismissing.

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Pathophysiology

4

Loss of SCUBE3 BMP Co-Receptor Function

Biallelic inactivating SCUBE3 variants remove a membrane-associated BMP2/4 co-receptor. Wild-type SCUBE3 attracts BMP receptor complexes to lipid-raft microdomains and enhances BMP signalling, apparently by facilitating the interaction of BMP ligands with BMP type I receptors. The best-characterized illustration of what that loss costs at the protein level is the N294K substitution, which reaches the cell surface normally but fails to complex with BMP type IA receptor - so the defect is in receptor engagement, not in protein trafficking. Read that as mechanism rather than as a patient variant: N294K is a mouse ENU-induced allele and is not among the human variants this entry curates. It is informative here because it sits in the cbEGF7 calcium-binding repeat, the same module the human missense alleles disrupt.

SCUBE3 hgnc:13655

BMP signaling pathway GO:0030509 ↓ DECREASED

Animal models

Scube3 N294K mouse (kta41) Mouse recapitulates Produces skeletal morphological abnormalities and altered bone-metabolism parameters, and its allele's receptor-binding defect is characterized.

Downstream

Impaired BMP-Mediated Chondrogenesis and Osteogenesis Loss of the co-receptor lowers BMP/SMAD output in the cells that build cartilage and bone. Two independent lines make this edge rather than the nodes alone: knocking SCUBE3 down in human bone-marrow mesenchymal stem cells blocks osteogenic differentiation, and the disease-associated alleles themselves reduce SMAD transactivation in vitro.

Impaired BMP-Driven Odontoblast Differentiation The dental arm of the same co-receptor loss. Scube3 is a tooth-germ epithelial transcript, and epithelium-derived SCUBE3 drives odontoblastic differentiation of dental mesenchyme through BMP2 signalling.

Show evidence (5 references)

PMID:33308444 SUPPORT In Vitro

"We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors."

The primary functional demonstration of the co-receptor role, from the gene-discovery cohort study.

PMID:33308444 SUPPORT In Vitro

"In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling."

Establishes that the disease variants act through BMP signalling, with variable severity across alleles.

PMID:37237303 SUPPORT In Vitro

"membrane-associated SCUBE3 may function as a BMP2/4 coreceptor, attract BMP receptor complexes to raft microdomains, and enhance BMP signaling"

States the molecular function whose loss initiates the disease.

+ 2 more references

Impaired BMP-Mediated Chondrogenesis and Osteogenesis

Reduced BMP signalling impairs chondrogenesis and osteogenesis. Scube3 knockout mice show impaired BMP-mediated chondrogenesis and osteogenesis with craniofacial and dental abnormalities, decreased body size and faulty endochondral bone development - the same combination of skeletal, facial and dental findings seen in patients, which is what makes this a convincing mechanism rather than a plausible one.

chondrocyte CL:0000138 osteoblast CL:0000062

endochondral bone growth GO:0003416 ↓ DECREASED osteoblast differentiation GO:0001649 ↓ DECREASED

Experimental models

SCUBE3 loss- and gain-of-function in human bone marrow mesenchymal stem cells PRIMARY CELL CULTURE Knockdown impairs osteogenic differentiation; adding back recombinant SCUBE3 raises BMP2 and TGF-beta and restores osteogenic function through SMAD phosphorylation, which is the pathway the disease loses.

Animal models

Scube3 knockout mouse Mouse recapitulates Reproduces impaired BMP-mediated chondrogenesis and osteogenesis with craniofacial, dental and endochondral bone abnormalities and decreased body size.

Scube3 ENU mutant mouse (saturation mutagenesis screen) Mouse partially recapitulates Reproduces the axial skeletal arm - severe spine deformity, skeletal abnormalities and altered bone metabolism - and links the disease alleles to reduced SMAD transactivation.

Downstream

Reduced Growth with Craniofacial, Dental and Skeletal Anomalies

Microcephaly Reported in a molecularly confirmed case. Grouped here because cranial bone growth shares the osteogenic defect, but a neural growth mechanism has not been shown.

Radial bowing Long-bone shape abnormality attributed to the defective endochondral bone growth shown in the knockout. The human finding is a single case report, so the link is inferred from the shared chondro-osseous defect rather than demonstrated.

Irregular vertebral endplates The vertebral endplate is a growth-plate equivalent, so its irregularity is read as the vertebral expression of the same chondro-osseous defect. Inferred from a single case report, not demonstrated.

Narrow iliac wing The ilium forms by endochondral ossification, so its narrowing is attributed to the same defect. Inferred from a single case report, not demonstrated.

Show evidence (2 references)

PMID:33308444 SUPPORT Model Organism

"Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."

The knockout phenotype from the primary study, explicitly described as recapitulating the human disorder.

PMID:37237303 SUPPORT Model Organism

"our analysis of this knockout mouse revealed that it has impaired BMP-mediated chondrogenesis and osteogenesis, which result in craniofacial and dental abnormalities, decreased body size, and faulty endochondral bone development"

The knockout phenotype, matching the human findings across all four domains.

Impaired BMP-Driven Odontoblast Differentiation

The dental arm of the mechanism, which is separable from the bone arm rather than a restatement of it. Scube3 transcript in the developing tooth is epithelial, and the protein moves to the mesenchyme, so the defect is in an epithelial-to-mesenchymal instruction: without it, dental mesenchymal cells fail to differentiate into polarized odontoblasts. The epithelial side is affected too - Scube3 knockout ameloblasts are shorter and wider and lose their Tomes processes; ameloblasts are epithelial rather than the mesenchyme-derived odontoblasts this node is bound to, and are recorded here because ameloblast induction is a prerequisite for odontoblast differentiation. This is why dental anomalies are prominent enough to appear in the disorder's ISDS row rather than being an incidental finding. One caveat on how much this node claims. Nothing has been measured in SCUBE3-deficient human or mouse teeth at the odontoblast level: the Scube3 knockout reports dental defects clinically, and the odontoblast step is a sufficiency result in healthy cells read in reverse. The DECREASED modifiers on the two GO processes are therefore an inference from the direction of those experiments rather than a measured reduction.

odontoblast CL:0000060

odontoblast differentiation GO:0071895 ↓ DECREASED odontogenesis GO:0042476 ↓ DECREASED

Experimental models

Human dental pulp stem cell and pulp-dentin organoid odontoblast model ORGANOID Exogenous SCUBE3 accelerates polarized odontoblastic differentiation of human dental mesenchymal cells through BMP2 signalling.

Downstream

Dental anomalies Failure of polarized odontoblast differentiation is the cellular event behind the clinical dental findings.

Show evidence (2 references)

PMID:37189178 SUPPORT Model Organism

"whose transcript expression is restricted to the tooth germ epithelium during the development of embryonic mouse teeth, has been demonstrated to play a crucial role in the regulation of tooth development"

Places SCUBE3 in the tooth germ epithelium during odontogenesis, which is what makes an epithelial-to-mesenchymal instruction the right model here.

PMID:37189178 SUPPORT Model Organism

"the specific knockout of SCUBE3 leads to a decrease in height, increase in width of ameloblasts, and loss of representative Tomes processes"

The ameloblast side of the dental defect in the Scube3 knockout. Two caveats travel with it. Ameloblasts are epithelial, not the mesenchyme-derived odontoblasts this node is bound to, so it supports the node's dental scope rather than its cell type; ameloblast induction is a prerequisite for odontoblast differentiation, which is why it sits here. And the sentence is this paper's introduction reporting somebody else's knockout result rather than its own finding, so the primary report would be the better citation if it can be identified.

Reduced Growth with Craniofacial, Dental and Skeletal Anomalies

The clinical endpoint: reduced growth with a distinctive craniofacial appearance, dental anomalies and skeletal features.

Downstream

Short stature The growth endpoint of impaired BMP-driven endochondral bone formation.

Prenatal growth retardation Prenatal arm of the same growth deficit.

Distinctive facial features Craniofacial consequence, reproduced as craniofacial abnormality in the Scube3 knockout mouse.

Dental anomalies Dental consequence, also reproduced in the knockout mouse - BMP signalling is required for tooth development as well as bone. The cell-level step is curated separately as Impaired BMP-Driven Odontoblast Differentiation, which also feeds this phenotype.

Scoliosis Axial skeletal consequence; the Scube3 ENU mutant alleles cause spine deformity including severe kyphosis.

Show evidence (1 reference)

PMID:37237303 SUPPORT Human Clinical

"18 affected people from nine independent families who shared the same phenotype of unusual craniofacial features, short stature, skeletal deformities and dental abnormalities"

Defines the shared clinical phenotype across the discovery cohort.

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Pathograph

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

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Phenotypes

10

Head and Neck 3

Distinctive facial features VERY_FREQUENT Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"distinctive facial traits, such as long face, high arched eyebrows, epicanthus, blepharoptosis, hypotelorism, high nasal bridge, micrognathia, and large ears"

Enumerates the facial gestalt in a molecularly confirmed case.

Dental anomalies VERY_FREQUENT Abnormality of the dentition HP:0000164

Show evidence (1 reference)

PMID:37237303 SUPPORT Human Clinical

"short stature, skeletal deformities and dental abnormalities"

Dental anomalies are part of the shared phenotype across the discovery cohort.

Microcephaly OCCASIONAL HP:0000252

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"prenatal growth retardation, short stature, microcephaly, distinctive facial traits"

Microcephaly in a molecularly confirmed case; curated OCCASIONAL because it comes from a single report rather than the cohort description.

Limbs 1

Radial bowing HP:0002986

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"

Long-bone shape abnormality in a molecularly confirmed case, consistent with the defective endochondral bone growth this entry curates.

Musculoskeletal 4

Scoliosis FREQUENT HP:0002650

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing"

Skeletal findings in a molecularly confirmed case.

11 pairs of ribs HP:0000878

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"

Radiological findings in a molecularly confirmed case.

Irregular vertebral endplates HP:0003301

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"

Vertebral endplate irregularity in a molecularly confirmed case.

Narrow iliac wing HP:0002868

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"

Pelvic finding in a molecularly confirmed case.

Growth 2

Short stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:37237303 SUPPORT Human Clinical

"the same phenotype of unusual craniofacial features, short stature, skeletal deformities and dental abnormalities"

Short stature is part of the shared phenotype across nine families.

Prenatal growth retardation FREQUENT Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"The patient exhibited prenatal growth retardation, short stature, microcephaly, distinctive facial traits"

Prenatal onset in a molecularly confirmed case - the feature that places this disorder among the primordial dwarfisms.

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Genetic Associations

1

SCUBE3

Gene: SCUBE3 hgnc:13655 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:37237303 SUPPORT Human Clinical

"The discovered variations, which comprised missense, frameshift, nonsense, and canonical splice site modifications as well as a complicated intragenic rearrangement, were dispersed throughout the entire coding sequence of SCUBE3."

Characterizes the variant spectrum, which is dispersed rather than domain-restricted.

PMID:40331102 SUPPORT Computational

"Protein modeling using AlphaFold3 revealed disruption of a critical disulfide bridge within the seventh epidermal growth factor-like repeat, likely affecting protein stability."

Structural modelling of a novel missense allele. Classified COMPUTATIONAL because the mechanism claim rests on modelling rather than an assay, and the source hedges it as "likely".

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Diagnosis

1

Molecular genetic testing of SCUBE3 (Bi-allelic inactivating SCUBE3 variants)

A recognizable phenotype - reduced growth, skeletal features, a distinctive craniofacial appearance and dental anomalies were consistent across eighteen individuals from nine families - but one that was unrecognized until the gene was found, so the diagnosis is made by sequencing rather than by clinical criteria. Variants differ in how far they impair transcript processing, secretion and function, which is a caveat for interpreting a novel allele: an in-vitro effect that is partial is still consistent with disease.

molecular genetic testing NCIT:C15709

On which patients reach this test. In the one cohort that sorted short-stature genes by mechanism, SCUBE3 fell in the syndromic-short-stature subgroup worked up hypothesis-free, not in the GH-IGF-I axis subgroup worked up by candidate gene. That distinction is clinically load-bearing: an endocrine workup for growth failure will not reach this diagnosis, and the trigger for sequencing is syndromic features or consanguinity rather than the growth failure itself.

Show evidence (5 references)

PMID:33308444 SUPPORT Human Clinical

"Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies."

The consistent phenotype that makes the disorder recognizable once the diagnosis is known.

PMID:33308444 SUPPORT In Vitro

"In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling."

The variable functional impact that complicates interpretation of a novel variant.

PMID:38838658 SUPPORT Human Clinical

"In the two siblings in family 25, we discovered a homozygous novel SCUBE3 variant, which at that time had not been described as a cause of short stature."

Shows the route by which this diagnosis is actually reached: hypothesis-free exome sequencing in a consanguineous child with syndromic short stature, not a clinical suspicion of the syndrome.

+ 2 more references

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Prevalence

1

Worldwide

Cases In Literature Not yet documented

Approximately 20 patients reported to date. No population rate published.

Show evidence (1 reference)

PMID:40331102 SUPPORT Human Clinical

"is a very rare genetic disorder caused by biallelic pathogenic variants in the SCUBE3 gene and has been reported in approximately 20 patients to date"

Gives the reported case count and confirms the recessive architecture.

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Related Datasets

1

A recessive point mutation is responsible for pleiotropic effects in a scube3 mutant mouse geo:GSE56402

Expression profiling from the Munich ENU kta41 line, the Scube3 N294K mouse curated above as an animal model. It is a mouse dataset carrying a mouse ENU allele, so it reports the model rather than the patients.

house mouse MICROARRAY

PMID:27815347

Surfaced by `just discover-datasets` as a GENE_ONLY match and kept after relevance triage: it profiles the Scube3 N294K mutant mouse, curated above as an animal model of this disorder, rather than merely mentioning the gene. N294K is a mouse ENU allele and not a patient variant, so the relevance runs through the model and not through a genotype match. The two other GENE_ONLY candidates from the same search were dropped - one is a SCUBE3 antibody cancer study and one an osteoporosis study - because neither concerns SCUBE3 loss of function in development.

Show evidence (1 reference)

GEO:GSE56402 SUPPORT Model Organism

"Whole genome sequencing approaches revealed a C to A transversion on position 882 in Scube3 that leads to a missense mutation in the protein (Asn294Lys)."

The repository record identifies the allele profiled as Scube3 N294K, which is what establishes the dataset's relevance to this entry.

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Experimental Models

2

SCUBE3 loss- and gain-of-function in human bone marrow mesenchymal stem cells PRIMARY_CELL_CULTURE

A human cell system that manipulates SCUBE3 in both directions in the cell type the disease affects. Its value here is the loss-of-function arm, which matches the disease; the study was designed around the gain-of-function arm for bone-defect repair, so most of its content is about a therapeutic use that this disorder does not have.

Organism

human NCBITaxon:9606

Cell source

primary human bone marrow mesenchymal stem cells

Culture

two-dimensional osteogenic differentiation culture

Publication

PMID:39250278

Pathograph links

Impaired BMP-Mediated Chondrogenesis and Osteogenesis perturbs fidelity: moderate observes: cellular Knockdown impairs osteogenic differentiation; adding back recombinant SCUBE3 raises BMP2 and TGF-beta and restores osteogenic function through SMAD phosphorylation, which is the pathway the disease loses.

Limitations: Healthy donor cells with SCUBE3 experimentally reduced, not patient cells carrying disease alleles, so it models the pathway loss rather than the genotype. It also reports only the osteogenic arm; nothing here addresses chondrogenesis, which is half of the target node.

Readouts

Osteogenic differentiation of hBMSCs after SCUBE3 knockdown

Direction: DECREASED

Interpretation: The loss-of-function arm, matching the direction of the human disease.

Show evidence (1 reference)

PMID:39250278 SUPPORT In Vitro

"SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation"

The measured effect of lowering SCUBE3 on osteogenic differentiation.

SMAD phosphorylation and osteogenic rescue by recombinant SCUBE3

Direction: RESTORED

Interpretation: A rescue arm showing the pathway is the operative one, not merely a correlate.

Show evidence (1 reference)

PMID:39250278 SUPPORT In Vitro

"treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation"

Adding the protein back restores the osteogenic output through SMAD, which is what makes this a pathway claim rather than an association.

Show evidence (1 reference)

PMID:39250278 SUPPORT In Vitro

"SCUBE3 fosters osteogenic differentiation and mitophagy in hBMSCs by activating the BMP2/TGF-β signaling pathway"

Supports treating this system as informative for the osteogenic half of the node.

Show evidence (1 reference)

PMID:39250278 SUPPORT In Vitro

"Our findings indicate that SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs"

The system's core result, and the reason it is informative here: SCUBE3 is regulated during the differentiation this disorder impairs.

Human dental pulp stem cell and pulp-dentin organoid odontoblast model ORGANOID

A human organoid system for the dental arm of the mechanism. It supplies the step the disease is missing rather than removing it, so the inference is a sufficiency argument read in reverse.

Organism

human NCBITaxon:9606

Cell source

primary human dental pulp stem cells from extracted premolars and third molars

Culture

pulp-dentin-like organoid and epithelial-mesenchymal co-culture

Publication

PMID:37189178

Pathograph links

Impaired BMP-Driven Odontoblast Differentiation perturbs fidelity: moderate observes: cellular Exogenous SCUBE3 accelerates polarized odontoblastic differentiation of human dental mesenchymal cells through BMP2 signalling.

Limitations: A gain-of-function system in healthy cells. It shows SCUBE3 is sufficient to drive odontoblastic differentiation; the disease claim is that its absence prevents it, which is the converse and is not tested here. No patient-derived dental cells have been reported.

Readouts

Polarized odontoblastic differentiation of human dental pulp stem cells

Direction: INCREASED

Interpretation: Added SCUBE3 raises odontoblastic differentiation, so the disease direction is the loss of that drive.

Show evidence (1 reference)

PMID:37189178 SUPPORT In Vitro

"In hDPSCs, exogenous SCUBE3 promoted cell proliferation and migration via TGF-β signalling and accelerated odontoblastic differentiation via BMP2 signalling."

The measured differentiation response to SCUBE3, and the pathway it runs through.

Show evidence (1 reference)

PMID:37189178 SUPPORT In Vitro

"Our results demonstrate that epithelium-derived SCUBE3 translocates to Mes via a paracrine pathway, accelerates proliferation, migration, and polarized odontoblastic differentiation of Mes, and promotes vascularized pulp regeneration."

The study's own summary of what this system showed, which is what makes it informative for the odontoblast node.

Show evidence (1 reference)

PMID:37189178 SUPPORT Model Organism

"In the semi-orthotopic animal experiments, we found that SCUBE3 pre-treatment-induced polarized odontoblast-like cells attached to the dental walls, and had better angiogenesis performance."

The system's in-vivo endpoint, showing SCUBE3-primed cells become polarized odontoblast-like cells. Note this arm of the study is an animal experiment, unlike the cell and organoid work the link evidence rests on.

🐁

Animal Models

3

Scube3 knockout mouse

A constitutive Scube3 null. Notably, homozygotes are born at expected Mendelian ratios and are viable and fertile, with no overt embryonic phenotype - the skeletal defect emerges on closer analysis rather than as a gross malformation.

Species

Mouse

Genotype

Scube3 null (tm1(KOMP)Vlcg)

Publication

PMID:37237303

Pathograph links

Impaired BMP-Mediated Chondrogenesis and Osteogenesis recapitulates fidelity: moderate Reproduces impaired BMP-mediated chondrogenesis and osteogenesis with craniofacial, dental and endochondral bone abnormalities and decreased body size.

Limitations: Much milder than the human disorder: the null mouse is viable and fertile with no overt embryonic phenotype, which the authors attribute to functional redundancy with other Scube family members. Mouse Scube3 also does not affect the hedgehog pathway, unlike zebrafish scube3, so cross-species inference about SCUBE pathway roles is unsafe.

Readouts

Body size

Direction: DECREASED

Interpretation: Organism-level correlate of the endochondral bone defect.

Show evidence (1 reference)

PMID:37237303 SUPPORT Model Organism

"decreased body size, and faulty endochondral bone development"

The measured growth outcome in the knockout.

Bone mineral density

Direction: DECREASED

Interpretation: Quantitative bone readout supporting the osteogenesis arm of the node.

Show evidence (1 reference)

PMID:37237303 SUPPORT Model Organism

"bone mineral density is markedly lower in Scube3-deficient"

The measured bone-density reduction in the knockout.

Show evidence (1 reference)

PMID:37237303 SUPPORT Model Organism

"impaired BMP-mediated chondrogenesis and osteogenesis, which result in craniofacial and dental abnormalities"

Supports treating this model as informative for the chondro-osteogenic node.

Show evidence (1 reference)

PMID:33308444 SUPPORT Model Organism

"Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."

Establishes the model itself, and the authors' own claim that it recapitulates the human disorder.

Scube3 ENU mutant mouse (saturation mutagenesis screen)

An independently derived allele, found by radiographic screening of an unbiased saturation-mutagenesis pedigree collection rather than by targeting the gene. That matters for how much weight the model carries: nobody was looking for SCUBE3, so the spine phenotype is not a result of an expectation. The same study then went the other way, matching the mouse to a previously undiagnosed patient carrying recessive SCUBE3 variants.

Species

Mouse

Genotype

Scube3 C301Y homozygous (recessive N-ethyl-N-nitrosourea-induced allele)

Publication

PMID:34142127

Pathograph links

Impaired BMP-Mediated Chondrogenesis and Osteogenesis partially recapitulates fidelity: moderate observes: organism Reproduces the axial skeletal arm - severe spine deformity, skeletal abnormalities and altered bone metabolism - and links the disease alleles to reduced SMAD transactivation.

Limitations: An ENU-induced missense allele (C301Y) rather than a null, and one not seen in a patient, so severity cannot be read across to the human loss-of-function alleles. It is a cbEGF7 substitution like N294K and is predicted to break a conserved disulfide bond, which is what makes it comparable to the human missense spectrum. The model was ascertained on spine deformity, so the craniofacial and dental domains that define the human syndrome are not reported for it.

Readouts

Spine deformity on radiographic screening

Direction: ALTERED

Interpretation: The axial skeletal correlate of the chondro-osseous defect, and the readout the model was ascertained on.

Show evidence (1 reference)

PMID:34142127 SUPPORT Model Organism

"we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3"

The measured skeletal outcome attributed to the recessive Scube3 allele.

SMAD transactivation by disease-associated SCUBE3 alleles

Direction: DECREASED

Interpretation: The signalling readout that connects the mouse allele to the human disease alleles through the same pathway.

Show evidence (1 reference)

PMID:34142127 SUPPORT In Vitro

"we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro"

Quantifies the reduced SMAD output produced by the disease alleles.

Show evidence (1 reference)

PMID:34142127 SUPPORT Model Organism

"Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3."

Supports treating this allele as informative for the chondro-osseous node.

Show evidence (3 references)

PMID:37237303 SUPPORT Model Organism

"another ENU-induced mutant allele (Scube3C301Y) was reported to cause recessive spine deformities, such as severe kyphosis and kinked tail"

Names the allele this line carries and the phenotype it produces.

PMID:37237303 SUPPORT Computational

"this C301Y mutation resides within the cbEGF7 domain, and it is expected to disrupt a key disulfide bond between conserved C2-C4 cysteines"

Places C301Y in the same cbEGF7 module as the human missense alleles and predicts the structural consequence. Graded COMPUTATIONAL because the disulfide claim is a structural expectation, hedged as "expected to".

PMID:37237303 SUPPORT Model Organism

"screening of mouse ENU-induced mutagenesis phenotypes led to the identification of recessive mutations in Scube3 on chromosome 17qA3.3 that confer severe spine deformity, skeleton abnormalities, and altered bone metabolism"

Independent summary of the ENU-derived Scube3 alleles and the phenotypes they produce. The plural is the review's own, and it cites two reports, so this sentence covers this line and the kta41 line together rather than picking out one; the spine-deformity clause is the part that belongs to this model.

Scube3 N294K mouse (kta41)

What separates this model from the other two is that its allele is characterized down to the protein interaction: N294K reaches the cell surface but fails to complex with BMP type IA receptor, so the mouse demonstrates the exact molecular step the trigger node asserts is lost. It is a domain match rather than an allele match, and the difference matters - N294K is an ENU-induced mouse allele, not a variant reported in a patient, but it falls in the cbEGF7 calcium-binding repeat, where several of the human missense alleles cluster. The line also arrived the other way round from most disease models: it was recovered from a morphological screen in the Munich ENU programme in 2016, four years before the human syndrome was described, so nobody chose this substitution to match a patient. Two of its findings sit outside what this entry curates as human phenotypes - hearing impairment and altered renal function. Neither is curated as a disease feature, because no cached source states either in patients; a deep-research report does describe recurrent conductive hearing loss in the discovery cohort, which this entry cannot quote. They are recorded here as model findings.

Species

Mouse

Genotype

Scube3 c.882C>A p.(Asn294Lys) homozygous (ENU-derived, line kta41)

Publication

PMID:27815347

Pathograph links

Loss of SCUBE3 BMP Co-Receptor Function recapitulates fidelity: moderate observes: organism Produces skeletal morphological abnormalities and altered bone-metabolism parameters, and its allele's receptor-binding defect is characterized.

Limitations: N294K is a mouse ENU allele rather than a variant seen in a patient, so the correspondence to the human disease runs through the affected domain (cbEGF7) and the demonstrated loss of BMP type IA receptor binding, not through the genotype. Being a single missense allele, it also says nothing about the frameshift, nonsense and splice-site variants that make up much of the human variant spectrum. The published phenotyping is a broad screening panel rather than a targeted skeletal study, and the paper frames the bone findings against Paget disease of bone rather than against this syndrome, which did not yet exist as an entity when it was written.

Readouts

Skeletal morphology and bone-metabolism parameters

Direction: ALTERED

Interpretation: The skeletal correlate of the co-receptor defect in an allele-matched animal.

Show evidence (1 reference)

PMID:27815347 SUPPORT Model Organism

"Scube3N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments."

The measured skeletal and bone-metabolism outcomes in the allele-matched mouse.

Show evidence (1 reference)

PMID:27815347 SUPPORT Model Organism

"Here, we present the first Scube3 mutant mouse line (Scube3N294K/N294K), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions."

Supports treating this line as informative for the molecular node, since it carries the substitution whose receptor-binding defect defines it.

Show evidence (2 references)

PMID:37237303 SUPPORT In Vitro

"the SCUBE3-N294K mutant protein is expressed on the cell surface, but it does not readily form a complex with the BMP type IA receptor"

Characterizes the allele this mouse carries at the level of the receptor interaction, which is what makes it informative for the molecular node.

PMID:37237303 SUPPORT Model Organism

"an asparagine-to-lysine exchange at protein position 294 (N294K) lies within the cbEGF7 repeat"

Locates the substitution in the cbEGF7 calcium-binding repeat. Recorded because that placement, not a genotype match with a patient, is what ties this mouse allele to the human missense spectrum.

{ }

Source YAML

click to show

name: SCUBE3-Related Short Stature Syndrome
creation_date: "2026-08-27T04:30:00Z"
category: Mendelian
synonyms:
- SSFSC2
- short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
- SCUBE3-related short stature-facial dysmorphism-skeletal and dental anomalies syndrome
description: >-
  A very rare autosomal recessive disorder of reduced growth with a distinctive
  craniofacial appearance, dental anomalies and skeletal deformities, caused by
  biallelic inactivating variants in SCUBE3. It is the mechanistic outlier of
  its nosology group: where the other primordial dwarfisms in ISDS group 21 run
  through DNA replication, centrosome biology or ubiquitin-mediated
  proteostasis, SCUBE3 encodes a secreted, membrane-associated BMP2/4
  co-receptor that concentrates BMP receptor complexes in lipid-raft
  microdomains and enhances BMP signalling. The defect is therefore in a
  growth-factor signalling pathway required for endochondral bone formation
  rather than in the cell cycle.

  Note a label collision worth checking before citing anything: MONDO:0100297 is
  SSFSC1 (OMIM 617877), a different gene and a different entity. The OMIM number
  619184 is what pins this one.
disease_term:
  preferred_term: short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
  term:
    id: MONDO:0030953
    label: short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
parents:
- Autosomal recessive disease
- Skeletal dysplasia
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  isds_skeletal_category:
  - classification_value: primordial_dwarfism_and_slender_bones
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 21 "Primordial dwarfism and slender bone
      dysplasias", NOS 21-0240 "Short stature, facial dysmorphism, skeletal and
      dental anomalies syndrome, SCUBE3-related" (AR, OMIM 619184). One row, one
      entry. The OMIM number is what identifies the row: MONDO:0100297 carries a
      near-identical label for SSFSC1 (OMIM 617877), which is a different gene
      and not in this group.


      On the "with or without cardiac anomalies" clause in the bound disease
      label: this entry curates no cardiac phenotype, but that is a limit of
      what can be verified here rather than a settled negative, and the earlier
      version of this note overstated it. What is true is that the sources this
      entry can quote say nothing about cardiac involvement - the abstract of
      the eighteen-patient discovery cohort (PMID:33308444) describes reduced
      growth, skeletal features, craniofacial appearance and dental anomalies
      and no cardiac finding, and its full text is not in the reference cache.
      What is not established is the stronger claim that no affected individual
      has one: two independent deep-research runs report atrial septal defect in
      two of the discovery cohort, tracing to HPO annotations on OMIM:619184
      rather than to any quotable sentence. That discrepancy is recorded as a
      discussion rather than resolved here, because resolving it needs full-text
      access nobody in this session had. Separately, two things in the
      literature look like cardiac evidence and are not. Cardiac and vascular
      biology in the SCUBE family is
      almost entirely SCUBE1 and SCUBE2 - different genes, and attributing it
      here would be Named Entity Confusion. The one genuine SCUBE3 cardiac
      result (reviewed in PMID:37237303) is cardiac hypertrophy in transgenic
      mice *overexpressing* SCUBE3 under a type I collagen promoter, appearing
      spontaneously at around eight months and augmented by pressure overload
      rather than requiring it. Either way the human disease is biallelic loss
      of function, so that is the opposite manipulation, and it would argue if
      anything that too little SCUBE3 protects the heart.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Approximately 20 patients reported to date. No population rate published.
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is a very rare genetic disorder caused by biallelic pathogenic variants in the SCUBE3 gene and has been reported in approximately 20 patients to date"
    explanation: >-
      Gives the reported case count and confirms the recessive architecture.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic inactivating SCUBE3 variants; reported families are frequently
    consanguineous.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight bi-allelic inactivating variants in SCUBE3 were first discovered and characterized by our research in 18 affected people from nine independent families who shared the same phenotype"
    explanation: >-
      Biallelic variants across nine independent families establish recessive
      inheritance.
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder."
    explanation: >-
      The primary source for the recessive, inactivating-variant architecture.
genetic:
- name: SCUBE3
  gene_term:
    preferred_term: SCUBE3
    term:
      id: hgnc:13655
      label: SCUBE3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    SCUBE3 (6p21.31) encodes a secreted and membrane-associated glycoprotein of
    the SCUBE family. Reported disease variants are missense, frameshift,
    nonsense, canonical splice-site changes and a complex intragenic
    rearrangement, dispersed across the whole coding sequence. Several missense
    variants cluster in the calcium-binding EGF-like repeats, where they disrupt
    disulfide bonds or calcium coordination and so impair the protein-protein
    interactions those domains mediate.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The discovered variations, which comprised missense, frameshift, nonsense, and canonical splice site modifications as well as a complicated intragenic rearrangement, were dispersed throughout the entire coding sequence of SCUBE3."
    explanation: >-
      Characterizes the variant spectrum, which is dispersed rather than
      domain-restricted.
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Protein modeling using AlphaFold3 revealed disruption of a critical disulfide bridge within the seventh epidermal growth factor-like repeat, likely affecting protein stability."
    explanation: >-
      Structural modelling of a novel missense allele. Classified COMPUTATIONAL
      because the mechanism claim rests on modelling rather than an assay, and
      the source hedges it as "likely".
pathophysiology:
- name: Loss of SCUBE3 BMP Co-Receptor Function
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Biallelic inactivating SCUBE3 variants remove a membrane-associated BMP2/4
    co-receptor. Wild-type SCUBE3 attracts BMP receptor complexes to lipid-raft
    microdomains and enhances BMP signalling, apparently by facilitating the
    interaction of BMP ligands with BMP type I receptors. The
    best-characterized illustration of what that loss costs at the protein level
    is the N294K substitution, which reaches the cell surface normally but fails
    to complex with BMP type IA receptor - so the defect is in receptor
    engagement, not in protein trafficking. Read that as mechanism rather than
    as a patient variant: N294K is a mouse ENU-induced allele and is not among
    the human variants this entry curates. It is informative here because it
    sits in the cbEGF7 calcium-binding repeat, the same module the human
    missense alleles disrupt.
  genes:
  - preferred_term: SCUBE3
    term:
      id: hgnc:13655
      label: SCUBE3
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  downstream:
  - target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
    causal_link_type: DIRECT
    description: >-
      Loss of the co-receptor lowers BMP/SMAD output in the cells that build
      cartilage and bone. Two independent lines make this edge rather than the
      nodes alone: knocking SCUBE3 down in human bone-marrow mesenchymal stem
      cells blocks osteogenic differentiation, and the disease-associated
      alleles themselves reduce SMAD transactivation in vitro.
    evidence:
    - reference: PMID:39250278
      reference_title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation"
      explanation: >-
        A loss-of-function manipulation in human osteogenic precursors, which is
        the same direction as the disease. Supports the edge rather than either
        node: removing SCUBE3 is what impairs the differentiation.
    - reference: PMID:34142127
      reference_title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro"
      explanation: >-
        Ties the disease alleles specifically to reduced SMAD transactivation,
        which is the signalling step this edge asserts.
    - reference: PMID:34142127
      reference_title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3"
      explanation: >-
        Establishes that the alleles assayed above are the human recessive ones,
        which is what lets the in-vitro result stand for the human disease.
        Split from the in-vitro clause because the two halves of that sentence
        are different kinds of evidence.
  - target: Impaired BMP-Driven Odontoblast Differentiation
    causal_link_type: DIRECT
    description: >-
      The dental arm of the same co-receptor loss. Scube3 is a tooth-germ
      epithelial transcript, and epithelium-derived SCUBE3 drives odontoblastic
      differentiation of dental mesenchyme through BMP2 signalling.
    evidence:
    - reference: PMID:37189178
      reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In hDPSCs, exogenous SCUBE3 promoted cell proliferation and migration via TGF-β signalling and accelerated odontoblastic differentiation via BMP2 signalling."
      directness: INDIRECT
      explanation: >-
        Establishes that SCUBE3 acts on odontoblastic differentiation through
        BMP2. Graded INDIRECT because it is a sufficiency result in healthy
        cells: the edge's claim that losing SCUBE3 impairs the step follows by
        inference, not from this experiment.
  evidence:
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors."
    explanation: >-
      The primary functional demonstration of the co-receptor role, from the
      gene-discovery cohort study.
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling."
    explanation: >-
      Establishes that the disease variants act through BMP signalling, with
      variable severity across alleles.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "membrane-associated SCUBE3 may function as a BMP2/4 coreceptor, attract BMP receptor complexes to raft microdomains, and enhance BMP signaling"
    explanation: >-
      States the molecular function whose loss initiates the disease.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the SCUBE3-N294K mutant protein is expressed on the cell surface, but it does not readily form a complex with the BMP type IA receptor"
    explanation: >-
      Localizes the defect to receptor engagement rather than to surface
      delivery, which is the distinction this node draws.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the gene is prominently expressed in human primary cultured osteoblasts"
    explanation: >-
      Expression profiling that explains why a ubiquitously available secreted
      co-receptor produces a skeletal phenotype: the gene is concentrated in the
      cell type that fails. Trimmed to the human cultured-osteoblast clause so
      the item carries one kind of evidence; the mouse long-bone half of the
      same sentence would be model-organism data.
- name: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
  biological_scale: TISSUE
  description: >-
    Reduced BMP signalling impairs chondrogenesis and osteogenesis. Scube3
    knockout mice show impaired BMP-mediated chondrogenesis and osteogenesis
    with craniofacial and dental abnormalities, decreased body size and faulty
    endochondral bone development - the same combination of skeletal, facial and
    dental findings seen in patients, which is what makes this a convincing
    mechanism rather than a plausible one.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: endochondral bone growth
    term:
      id: GO:0003416
      label: endochondral bone growth
    modifier: DECREASED
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  downstream:
  - target: Reduced Growth with Craniofacial, Dental and Skeletal Anomalies
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33308444
      reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
      explanation: >-
        The quoted sentence states the causal direction this edge asserts - the
        organism-level findings arise from the impaired chondrogenesis and
        osteogenesis, not merely alongside it.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reported in a molecularly confirmed case. Grouped here because cranial
      bone growth shares the osteogenic defect, but a neural growth mechanism
      has not been shown.
  - target: Radial bowing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Long-bone shape abnormality attributed to the defective endochondral bone
      growth shown in the knockout. The human finding is a single case report,
      so the link is inferred from the shared chondro-osseous defect rather
      than demonstrated.
  - target: Irregular vertebral endplates
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The vertebral endplate is a growth-plate equivalent, so its irregularity
      is read as the vertebral expression of the same chondro-osseous defect.
      Inferred from a single case report, not demonstrated.
  - target: Narrow iliac wing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The ilium forms by endochondral ossification, so its narrowing is
      attributed to the same defect. Inferred from a single case report, not
      demonstrated.
  evidence:
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
    explanation: >-
      The knockout phenotype from the primary study, explicitly described as
      recapitulating the human disorder.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our analysis of this knockout mouse revealed that it has impaired BMP-mediated chondrogenesis and osteogenesis, which result in craniofacial and dental abnormalities, decreased body size, and faulty endochondral bone development"
    explanation: >-
      The knockout phenotype, matching the human findings across all four
      domains.
- name: Impaired BMP-Driven Odontoblast Differentiation
  biological_scale: CELLULAR
  description: >-
    The dental arm of the mechanism, which is separable from the bone arm rather
    than a restatement of it. Scube3 transcript in the developing tooth is
    epithelial, and the protein moves to the mesenchyme, so the defect is in an
    epithelial-to-mesenchymal instruction: without it, dental mesenchymal cells
    fail to differentiate into polarized odontoblasts. The epithelial side is
    affected too - Scube3 knockout ameloblasts are shorter and wider and lose
    their Tomes processes; ameloblasts are epithelial rather than the
    mesenchyme-derived odontoblasts this node is bound to, and are recorded here
    because ameloblast induction is a prerequisite for odontoblast
    differentiation. This is why dental anomalies are prominent enough to appear
    in the disorder's ISDS row rather than being an incidental finding.


    One caveat on how much this node claims. Nothing has been measured in
    SCUBE3-deficient human or mouse teeth at the odontoblast level: the Scube3
    knockout reports dental defects clinically, and the odontoblast step is a
    sufficiency result in healthy cells read in reverse. The DECREASED modifiers
    on the two GO processes are therefore an inference from the direction of
    those experiments rather than a measured reduction.
  cell_types:
  - preferred_term: odontoblast
    term:
      id: CL:0000060
      label: odontoblast
  biological_processes:
  - preferred_term: odontoblast differentiation
    term:
      id: GO:0071895
      label: odontoblast differentiation
    modifier: DECREASED
  - preferred_term: odontogenesis
    term:
      id: GO:0042476
      label: odontogenesis
    modifier: DECREASED
  downstream:
  - target: Dental anomalies
    causal_link_type: DIRECT
    description: >-
      Failure of polarized odontoblast differentiation is the cellular event
      behind the clinical dental findings.
    evidence:
    - reference: PMID:33308444
      reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
      explanation: >-
        Removing Scube3 produces dental defects, which is the direction this
        edge asserts. The cited sentence names the clinical-level outcome, not
        the odontoblast step, so the cell-level attribution rests on the node's
        own evidence rather than on this quote.
    - reference: PMID:37189178
      reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "exogenous SCUBE3 promoted cell proliferation and migration via TGF-β signalling and accelerated odontoblastic differentiation via BMP2 signalling"
      explanation: >-
        Graded INDIRECT because the experiment is the converse of the disease:
        it shows SCUBE3 is sufficient to drive odontoblastic differentiation in
        healthy human cells, from which the edge infers that losing it impairs
        that step.
  evidence:
  - reference: PMID:37189178
    reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "whose transcript expression is restricted to the tooth germ epithelium during the development of embryonic mouse teeth, has been demonstrated to play a crucial role in the regulation of tooth development"
    explanation: >-
      Places SCUBE3 in the tooth germ epithelium during odontogenesis, which is
      what makes an epithelial-to-mesenchymal instruction the right model here.
  - reference: PMID:37189178
    reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the specific knockout of SCUBE3 leads to a decrease in height, increase in width of ameloblasts, and loss of representative Tomes processes"
    explanation: >-
      The ameloblast side of the dental defect in the Scube3 knockout. Two
      caveats travel with it. Ameloblasts are epithelial, not the
      mesenchyme-derived odontoblasts this node is bound to, so it supports the
      node's dental scope rather than its cell type; ameloblast induction is a
      prerequisite for odontoblast differentiation, which is why it sits here.
      And the sentence is this paper's introduction reporting somebody else's
      knockout result rather than its own finding, so the primary report would
      be the better citation if it can be identified.
- name: Reduced Growth with Craniofacial, Dental and Skeletal Anomalies
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoint: reduced growth with a distinctive craniofacial
    appearance, dental anomalies and skeletal features.
  downstream:
  - target: Short stature
    description: >-
      The growth endpoint of impaired BMP-driven endochondral bone formation.
    evidence:
    - reference: PMID:33308444
      reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
      explanation: >-
        The reduced body size in the knockout is attributed to the same
        endochondral bone defect, which is the step this edge asserts.
  - target: Prenatal growth retardation
    description: >-
      Prenatal arm of the same growth deficit.
  - target: Distinctive facial features
    description: >-
      Craniofacial consequence, reproduced as craniofacial abnormality in the
      Scube3 knockout mouse.
    evidence:
    - reference: PMID:33308444
      reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
      explanation: >-
        Craniofacial defects arise in the knockout from the same impaired
        chondrogenesis and osteogenesis this node summarizes.
  - target: Dental anomalies
    description: >-
      Dental consequence, also reproduced in the knockout mouse - BMP
      signalling is required for tooth development as well as bone. The
      cell-level step is curated separately as Impaired BMP-Driven Odontoblast
      Differentiation, which also feeds this phenotype.
    evidence:
    - reference: PMID:33308444
      reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
      explanation: >-
        Dental defects accompany the skeletal defects in the knockout, from the
        same BMP-dependent mechanism.
  - target: Scoliosis
    description: >-
      Axial skeletal consequence; the Scube3 ENU mutant alleles cause spine
      deformity including severe kyphosis.
    evidence:
    - reference: PMID:34142127
      reference_title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3"
      explanation: >-
        An independent recessive Scube3 allele produces spine deformity, which
        is the causal claim this edge makes rather than a co-occurrence.
    - reference: PMID:37237303
      reference_title: "The biology of SCUBE."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "screening of mouse ENU-induced mutagenesis phenotypes led to the identification of recessive mutations in Scube3 on chromosome 17qA3.3 that confer severe spine deformity, skeleton abnormalities, and altered bone metabolism"
      explanation: >-
        The review's account of the same ENU result, which is the source the
        node description was drawing on.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 affected people from nine independent families who shared the same phenotype of unusual craniofacial features, short stature, skeletal deformities and dental abnormalities"
    explanation: >-
      Defines the shared clinical phenotype across the discovery cohort.
phenotypes:
- category: Growth
  name: Short stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the same phenotype of unusual craniofacial features, short stature, skeletal deformities and dental abnormalities"
    explanation: >-
      Short stature is part of the shared phenotype across nine families.
- category: Growth
  name: Prenatal growth retardation
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  frequency: FREQUENT
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient exhibited prenatal growth retardation, short stature, microcephaly, distinctive facial traits"
    explanation: >-
      Prenatal onset in a molecularly confirmed case - the feature that places
      this disorder among the primordial dwarfisms.
- category: Craniofacial
  name: Distinctive facial features
  phenotype_term:
    preferred_term: Distinctive craniofacial appearance
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Reported features include a long face, high-arched eyebrows, epicanthus,
    blepharoptosis, hypotelorism, a high nasal bridge, micrognathia and large
    ears.
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinctive facial traits, such as long face, high arched eyebrows, epicanthus, blepharoptosis, hypotelorism, high nasal bridge, micrognathia, and large ears"
    explanation: >-
      Enumerates the facial gestalt in a molecularly confirmed case.
- category: Dental
  name: Dental anomalies
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Prominent enough to be named in the disorder's ISDS row, and reproduced in
    the Scube3 knockout mouse - unusual among the group-21 disorders, most of
    which have no dental component.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature, skeletal deformities and dental abnormalities"
    explanation: >-
      Dental anomalies are part of the shared phenotype across the discovery
      cohort.
- category: Skeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing"
    explanation: >-
      Skeletal findings in a molecularly confirmed case.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prenatal growth retardation, short stature, microcephaly, distinctive facial traits"
    explanation: >-
      Microcephaly in a molecularly confirmed case; curated OCCASIONAL because
      it comes from a single report rather than the cohort description.
- category: Skeletal
  name: 11 pairs of ribs
  phenotype_term:
    preferred_term: 11 pairs of ribs
    term:
      id: HP:0000878
      label: 11 pairs of ribs
  description: >-
    An axial patterning defect rather than a growth deficit, and the finding in
    this entry that is least explained by the endochondral-growth mechanism:
    rib number is set during somitogenesis, before the growth plate exists.
    Frequency is left unset because it comes from a single radiologically
    characterized case rather than from the cohort.
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"
    explanation: >-
      Radiological findings in a molecularly confirmed case.
- category: Skeletal
  name: Radial bowing
  phenotype_term:
    preferred_term: Radial bowing
    term:
      id: HP:0002986
      label: Radial bowing
  description: >-
    Described as mild in the reported case.
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"
    explanation: >-
      Long-bone shape abnormality in a molecularly confirmed case, consistent
      with the defective endochondral bone growth this entry curates.
- category: Skeletal
  name: Irregular vertebral endplates
  phenotype_term:
    preferred_term: Irregular vertebral endplates
    term:
      id: HP:0003301
      label: Irregular vertebral endplates
  description: >-
    Reported in the lower thoracic spine. The endplate is a growth-plate
    equivalent for the vertebral body, so an irregular endplate is the
    radiological signature of the same chondro-osseous defect that produces the
    long-bone findings, rather than a separate lesion.
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"
    explanation: >-
      Vertebral endplate irregularity in a molecularly confirmed case.
- category: Skeletal
  name: Narrow iliac wing
  phenotype_term:
    preferred_term: Narrow iliac wing
    term:
      id: HP:0002868
      label: Narrow iliac wing
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"
    explanation: >-
      Pelvic finding in a molecularly confirmed case.
diagnosis:
- name: Molecular genetic testing of SCUBE3
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: Bi-allelic inactivating SCUBE3 variants
  notes: >-
    On which patients reach this test. In the one cohort that sorted
    short-stature genes by mechanism, SCUBE3 fell in the syndromic-short-stature
    subgroup worked up hypothesis-free, not in the GH-IGF-I axis subgroup worked
    up by candidate gene. That distinction is clinically load-bearing: an
    endocrine workup for growth failure will not reach this diagnosis, and the
    trigger for sequencing is syndromic features or consanguinity rather than
    the growth failure itself.
  description: >-
    A recognizable phenotype - reduced growth, skeletal features, a distinctive
    craniofacial appearance and dental anomalies were consistent across
    eighteen individuals from nine families - but one that was unrecognized
    until the gene was found, so the diagnosis is made by sequencing rather
    than by clinical criteria. Variants differ in how far they impair transcript
    processing, secretion and function, which is a caveat for interpreting a
    novel allele: an in-vitro effect that is partial is still consistent with
    disease.
  evidence:
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies."
    explanation: >-
      The consistent phenotype that makes the disorder recognizable once the
      diagnosis is known.
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling."
    explanation: >-
      The variable functional impact that complicates interpretation of a novel
      variant.
  - reference: PMID:38838658
    reference_title: "Genetic Findings in Short Turkish Children Born to Consanguineous Parents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the two siblings in family 25, we discovered a homozygous novel SCUBE3 variant, which at that time had not been described as a cause of short stature."
    explanation: >-
      Shows the route by which this diagnosis is actually reached:
      hypothesis-free exome sequencing in a consanguineous child with syndromic
      short stature, not a clinical suspicion of the syndrome.
  - reference: PMID:38838658
    reference_title: "Genetic Findings in Short Turkish Children Born to Consanguineous Parents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions."
    explanation: >-
      Places SCUBE3 in the syndromic-short-stature subgroup rather than the
      GH-IGF-I axis subgroup, which is the referral distinction recorded in the
      notes above.
  - reference: PMID:39706863
    reference_title: "Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "noted novel gene-disease relationships for PISD, BNIP1, TONSL, CCN2 and SCUBE3 related skeletal dysplasia"
    explanation: >-
      An independent large skeletal-dysplasia cohort reaching the same gene by
      sequencing, which is corroboration that the sequencing-first route works
      rather than a second description of the phenotype.
experimental_models:
- name: SCUBE3 loss- and gain-of-function in human bone marrow mesenchymal stem cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: primary human bone marrow mesenchymal stem cells
  culture_system: two-dimensional osteogenic differentiation culture
  publication: PMID:39250278
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: mesenchymal stem cell of the bone marrow
    term:
      id: CL:0002540
      label: mesenchymal stem cell of the bone marrow
  conditions:
  - SCUBE3 knockdown
  - SCUBE3 overexpression
  - recombinant human SCUBE3 treatment
  description: >-
    A human cell system that manipulates SCUBE3 in both directions in the cell
    type the disease affects. Its value here is the loss-of-function arm, which
    matches the disease; the study was designed around the gain-of-function arm
    for bone-defect repair, so most of its content is about a therapeutic use
    that this disorder does not have.
  modeled_mechanisms:
  - target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Knockdown impairs osteogenic differentiation; adding back recombinant
      SCUBE3 raises BMP2 and TGF-beta and restores osteogenic function through
      SMAD phosphorylation, which is the pathway the disease loses.
    limitations: >-
      Healthy donor cells with SCUBE3 experimentally reduced, not patient cells
      carrying disease alleles, so it models the pathway loss rather than the
      genotype. It also reports only the osteogenic arm; nothing here addresses
      chondrogenesis, which is half of the target node.
    readouts:
    - name: Osteogenic differentiation of hBMSCs after SCUBE3 knockdown
      target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
      direction: DECREASED
      interpretation: >-
        The loss-of-function arm, matching the direction of the human disease.
      evidence:
      - reference: PMID:39250278
        reference_title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation"
        explanation: >-
          The measured effect of lowering SCUBE3 on osteogenic differentiation.
    - name: SMAD phosphorylation and osteogenic rescue by recombinant SCUBE3
      target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
      direction: RESTORED
      interpretation: >-
        A rescue arm showing the pathway is the operative one, not merely a
        correlate.
      evidence:
      - reference: PMID:39250278
        reference_title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation"
        explanation: >-
          Adding the protein back restores the osteogenic output through SMAD,
          which is what makes this a pathway claim rather than an association.
    evidence:
    - reference: PMID:39250278
      reference_title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SCUBE3 fosters osteogenic differentiation and mitophagy in hBMSCs by activating the BMP2/TGF-β signaling pathway"
      explanation: >-
        Supports treating this system as informative for the osteogenic half of
        the node.
  evidence:
  - reference: PMID:39250278
    reference_title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings indicate that SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs"
    explanation: >-
      The system's core result, and the reason it is informative here: SCUBE3 is
      regulated during the differentiation this disorder impairs.
- name: Human dental pulp stem cell and pulp-dentin organoid odontoblast model
  experimental_model_type: ORGANOID
  cell_source: primary human dental pulp stem cells from extracted premolars and third molars
  culture_system: pulp-dentin-like organoid and epithelial-mesenchymal co-culture
  publication: PMID:37189178
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: odontoblast
    term:
      id: CL:0000060
      label: odontoblast
  conditions:
  - recombinant human SCUBE3 treatment
  - tooth germ epithelium and mesenchyme co-culture
  description: >-
    A human organoid system for the dental arm of the mechanism. It supplies the
    step the disease is missing rather than removing it, so the inference is a
    sufficiency argument read in reverse.
  modeled_mechanisms:
  - target: Impaired BMP-Driven Odontoblast Differentiation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Exogenous SCUBE3 accelerates polarized odontoblastic differentiation of
      human dental mesenchymal cells through BMP2 signalling.
    limitations: >-
      A gain-of-function system in healthy cells. It shows SCUBE3 is sufficient
      to drive odontoblastic differentiation; the disease claim is that its
      absence prevents it, which is the converse and is not tested here. No
      patient-derived dental cells have been reported.
    readouts:
    - name: Polarized odontoblastic differentiation of human dental pulp stem cells
      target: Impaired BMP-Driven Odontoblast Differentiation
      direction: INCREASED
      interpretation: >-
        Added SCUBE3 raises odontoblastic differentiation, so the disease
        direction is the loss of that drive.
      evidence:
      - reference: PMID:37189178
        reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "In hDPSCs, exogenous SCUBE3 promoted cell proliferation and migration via TGF-β signalling and accelerated odontoblastic differentiation via BMP2 signalling."
        explanation: >-
          The measured differentiation response to SCUBE3, and the pathway it
          runs through.
    evidence:
    - reference: PMID:37189178
      reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our results demonstrate that epithelium-derived SCUBE3 translocates to Mes via a paracrine pathway, accelerates proliferation, migration, and polarized odontoblastic differentiation of Mes, and promotes vascularized pulp regeneration."
      explanation: >-
        The study's own summary of what this system showed, which is what makes
        it informative for the odontoblast node.
  evidence:
  - reference: PMID:37189178
    reference_title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the semi-orthotopic animal experiments, we found that SCUBE3 pre-treatment-induced polarized odontoblast-like cells attached to the dental walls, and had better angiogenesis performance."
    explanation: >-
      The system's in-vivo endpoint, showing SCUBE3-primed cells become
      polarized odontoblast-like cells. Note this arm of the study is an animal
      experiment, unlike the cell and organoid work the link evidence rests on.
animal_models:
- name: Scube3 knockout mouse
  species: Mouse
  genotype: Scube3 null (tm1(KOMP)Vlcg)
  publication: PMID:37237303
  description: >-
    A constitutive Scube3 null. Notably, homozygotes are born at expected
    Mendelian ratios and are viable and fertile, with no overt embryonic
    phenotype - the skeletal defect emerges on closer analysis rather than as a
    gross malformation.
  modeled_mechanisms:
  - target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces impaired BMP-mediated chondrogenesis and osteogenesis with
      craniofacial, dental and endochondral bone abnormalities and decreased
      body size.
    limitations: >-
      Much milder than the human disorder: the null mouse is viable and fertile
      with no overt embryonic phenotype, which the authors attribute to
      functional redundancy with other Scube family members. Mouse Scube3 also
      does not affect the hedgehog pathway, unlike zebrafish scube3, so
      cross-species inference about SCUBE pathway roles is unsafe.
    readouts:
    - name: Body size
      target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
      direction: DECREASED
      interpretation: >-
        Organism-level correlate of the endochondral bone defect.
      evidence:
      - reference: PMID:37237303
        reference_title: "The biology of SCUBE."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "decreased body size, and faulty endochondral bone development"
        explanation: >-
          The measured growth outcome in the knockout.
    - name: Bone mineral density
      target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
      direction: DECREASED
      interpretation: >-
        Quantitative bone readout supporting the osteogenesis arm of the node.
      evidence:
      - reference: PMID:37237303
        reference_title: "The biology of SCUBE."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "bone mineral density is markedly lower in Scube3-deficient"
        explanation: >-
          The measured bone-density reduction in the knockout.
    evidence:
    - reference: PMID:37237303
      reference_title: "The biology of SCUBE."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "impaired BMP-mediated chondrogenesis and osteogenesis, which result in craniofacial and dental abnormalities"
      explanation: >-
        Supports treating this model as informative for the chondro-osteogenic
        node.
  evidence:
  - reference: PMID:33308444
    reference_title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder."
    explanation: >-
      Establishes the model itself, and the authors' own claim that it
      recapitulates the human disorder.
- name: Scube3 ENU mutant mouse (saturation mutagenesis screen)
  species: Mouse
  genotype: Scube3 C301Y homozygous (recessive N-ethyl-N-nitrosourea-induced allele)
  publication: PMID:34142127
  description: >-
    An independently derived allele, found by radiographic screening of an
    unbiased saturation-mutagenesis pedigree collection rather than by targeting
    the gene. That matters for how much weight the model carries: nobody was
    looking for SCUBE3, so the spine phenotype is not a result of an expectation.
    The same study then went the other way, matching the mouse to a previously
    undiagnosed patient carrying recessive SCUBE3 variants.
  modeled_mechanisms:
  - target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the axial skeletal arm - severe spine deformity, skeletal
      abnormalities and altered bone metabolism - and links the disease alleles
      to reduced SMAD transactivation.
    limitations: >-
      An ENU-induced missense allele (C301Y) rather than a null, and one not
      seen in a patient, so severity cannot be read across to the human
      loss-of-function alleles. It is a cbEGF7 substitution like N294K and is
      predicted to break a conserved disulfide bond, which is what makes it
      comparable to the human missense spectrum. The model was ascertained on
      spine deformity, so the craniofacial and dental domains that define the
      human syndrome are not reported for it.
    readouts:
    - name: Spine deformity on radiographic screening
      target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
      direction: ALTERED
      interpretation: >-
        The axial skeletal correlate of the chondro-osseous defect, and the
        readout the model was ascertained on.
      evidence:
      - reference: PMID:34142127
        reference_title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3"
        explanation: >-
          The measured skeletal outcome attributed to the recessive Scube3
          allele.
    - name: SMAD transactivation by disease-associated SCUBE3 alleles
      target: Impaired BMP-Mediated Chondrogenesis and Osteogenesis
      direction: DECREASED
      interpretation: >-
        The signalling readout that connects the mouse allele to the human
        disease alleles through the same pathway.
      evidence:
      - reference: PMID:34142127
        reference_title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro"
        explanation: >-
          Quantifies the reduced SMAD output produced by the disease alleles.
    evidence:
    - reference: PMID:34142127
      reference_title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3."
      explanation: >-
        Supports treating this allele as informative for the chondro-osseous
        node.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "another ENU-induced mutant allele (Scube3C301Y) was reported to cause recessive spine deformities, such as severe kyphosis and kinked tail"
    explanation: >-
      Names the allele this line carries and the phenotype it produces.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "this C301Y mutation resides within the cbEGF7 domain, and it is expected to disrupt a key disulfide bond between conserved C2-C4 cysteines"
    explanation: >-
      Places C301Y in the same cbEGF7 module as the human missense alleles and
      predicts the structural consequence. Graded COMPUTATIONAL because the
      disulfide claim is a structural expectation, hedged as "expected to".
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "screening of mouse ENU-induced mutagenesis phenotypes led to the identification of recessive mutations in Scube3 on chromosome 17qA3.3 that confer severe spine deformity, skeleton abnormalities, and altered bone metabolism"
    explanation: >-
      Independent summary of the ENU-derived Scube3 alleles and the phenotypes
      they produce. The plural is the review's own, and it cites two reports, so
      this sentence covers this line and the kta41 line together rather than
      picking out one; the spine-deformity clause is the part that belongs to
      this model.
- name: Scube3 N294K mouse (kta41)
  species: Mouse
  genotype: Scube3 c.882C>A p.(Asn294Lys) homozygous (ENU-derived, line kta41)
  publication: PMID:27815347
  description: >-
    What separates this model from the other two is that its allele is
    characterized down to the protein interaction: N294K reaches the cell
    surface but fails to complex with BMP type IA receptor, so the mouse
    demonstrates the exact molecular step the trigger node asserts is lost. It
    is a domain match rather than an allele match, and the difference matters -
    N294K is an ENU-induced mouse allele, not a variant reported in a patient,
    but it falls in the cbEGF7 calcium-binding repeat, where several of the
    human missense alleles cluster. The line also arrived the other way round
    from most disease models: it was recovered from a morphological screen in
    the Munich ENU programme in 2016, four years before the human syndrome was
    described, so nobody chose this substitution to match a patient. Two of its
    findings sit outside what this entry curates as human phenotypes - hearing
    impairment and altered renal function. Neither is curated as a disease
    feature, because no cached source states either in patients; a
    deep-research report does describe recurrent conductive hearing loss in the
    discovery cohort, which this entry cannot quote. They are recorded here as
    model findings.
  modeled_mechanisms:
  - target: Loss of SCUBE3 BMP Co-Receptor Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Produces skeletal morphological abnormalities and altered bone-metabolism
      parameters, and its allele's receptor-binding defect is characterized.
    limitations: >-
      N294K is a mouse ENU allele rather than a variant seen in a patient, so
      the correspondence to the human disease runs through the affected domain
      (cbEGF7) and the demonstrated loss of BMP type IA receptor binding, not
      through the genotype. Being a single missense allele, it also says nothing
      about the frameshift, nonsense and splice-site variants that make up much
      of the human variant spectrum. The published phenotyping is a broad
      screening panel rather than a targeted skeletal study, and the paper
      frames the bone findings against Paget disease of bone rather than against
      this syndrome, which did not yet exist as an entity when it was written.
    readouts:
    - name: Skeletal morphology and bone-metabolism parameters
      target: Loss of SCUBE3 BMP Co-Receptor Function
      direction: ALTERED
      interpretation: >-
        The skeletal correlate of the co-receptor defect in an allele-matched
        animal.
      evidence:
      - reference: PMID:27815347
        reference_title: "The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Scube3N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments."
        explanation: >-
          The measured skeletal and bone-metabolism outcomes in the
          allele-matched mouse.
    evidence:
    - reference: PMID:27815347
      reference_title: "The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we present the first Scube3 mutant mouse line (Scube3N294K/N294K), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions."
      explanation: >-
        Supports treating this line as informative for the molecular node, since
        it carries the substitution whose receptor-binding defect defines it.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the SCUBE3-N294K mutant protein is expressed on the cell surface, but it does not readily form a complex with the BMP type IA receptor"
    explanation: >-
      Characterizes the allele this mouse carries at the level of the receptor
      interaction, which is what makes it informative for the molecular node.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "an asparagine-to-lysine exchange at protein position 294 (N294K) lies within the cbEGF7 repeat"
    explanation: >-
      Locates the substitution in the cbEGF7 calcium-binding repeat. Recorded
      because that placement, not a genotype match with a patient, is what ties
      this mouse allele to the human missense spectrum.
datasets:
- accession: geo:GSE56402
  title: A recessive point mutation is responsible for pleiotropic effects in a scube3 mutant mouse
  data_type: MICROARRAY
  description: >-
    Expression profiling from the Munich ENU kta41 line, the Scube3 N294K mouse
    curated above as an animal model. It is a mouse dataset carrying a mouse ENU
    allele, so it reports the model rather than the patients.
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:27815347
  notes: >-
    Surfaced by `just discover-datasets` as a GENE_ONLY match and kept after
    relevance triage: it profiles the Scube3 N294K mutant mouse, curated above
    as an animal model of this disorder, rather than merely mentioning the gene.
    N294K is a mouse ENU allele and not a patient variant, so the relevance runs
    through the model and not through a genotype match. The two other GENE_ONLY
    candidates from the same search were dropped - one is a SCUBE3 antibody
    cancer study and one an osteoporosis study - because neither concerns SCUBE3
    loss of function in development.
  evidence:
  - reference: GEO:GSE56402
    reference_title: "A recessive point mutation is responsible for pleiotropic effects in a scube3 mutant mouse"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Whole genome sequencing approaches revealed a C to A transversion on position 882 in Scube3 that leads to a missense mutation in the protein (Asn294Lys)."
    explanation: >-
      The repository record identifies the allele profiled as Scube3 N294K,
      which is what establishes the dataset's relevance to this entry.
discussions:
- discussion_id: scube3_mouse_null_milder_than_human
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is the Scube3 null mouse viable, fertile and grossly normal at birth
    when biallelic SCUBE3 loss in humans produces prenatal growth restriction
    and a recognizable multisystem syndrome?
  attaches_to:
  - pathophysiology#Impaired BMP-Mediated Chondrogenesis and Osteogenesis
  - animal_models#Scube3 knockout mouse
  rationale: >-
    This is a mismatch in severity rather than in kind: the knockout does
    reproduce the craniofacial, dental and endochondral domains, so the model is
    informative, but it does not reproduce how much they cost the organism. The
    standing explanation is redundancy with the other SCUBE family members, and
    the zebrafish work makes that concrete - single scube mutants are mild while
    triple mutants approach a complete Hedgehog loss-of-function phenotype. That
    explanation has a consequence for interpreting this disease, which is why it
    is worth recording rather than filing as a caveat: if compensation by SCUBE1
    and SCUBE2 sets how severe a given individual is, then the variable
    expressivity in patients may be modifier-driven rather than allele-driven,
    and no study has tested that. Note also that the zebrafish result is
    Hedgehog, not BMP, and mouse Scube3 does not affect Hedgehog - so the
    redundancy argument is being carried across species and across pathways, and
    it has not been shown for BMP in mammals.
  evidence:
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mice that are homozygous for the tm1(KOPM)Vlcg allele (Scube3−/−) are born at expected Mendelian ratios, show no overt embryonic phenotypes, and are both viable and fertile"
    explanation: >-
      The half of the mismatch that concerns the mouse: the null is viable,
      fertile and grossly normal at birth.
  - reference: PMID:37237303
    reference_title: "The biology of SCUBE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mouse Scube3 does not appear to affect the HH pathway, unlike zebrafish scube3"
    explanation: >-
      Sources this discussion's own caveat against itself: the redundancy
      argument is carried from a Hedgehog result in zebrafish to a BMP claim in
      mammals, and this sentence is why that step is not safe.
  - reference: PMID:40912446
    reference_title: "Redundant and novel functions of scube genes during zebrafish development."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Individual functional characterisation has proved challenging because of overlapping expression patterns and compensatory mechanisms that likely obscure specific roles."
    explanation: >-
      States the compensation problem the redundancy explanation rests on.
      Graded OTHER because the sentence describes the difficulty of the research
      rather than reporting a zebrafish result, and INDIRECT because it is the
      premise of the argument rather than a demonstration of it.
  - reference: PMID:40912446
    reference_title: "Redundant and novel functions of scube genes during zebrafish development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "all three Scube proteins contribute to muscle development at distinct levels, with triple knockout zebrafish larvae displaying near-complete Hedgehog loss-of-function phenotypes"
    explanation: >-
      The concrete demonstration that removing one family member understates the
      pathway's role, which is the argument for why the single mouse null is
      mild. Note this is a Hedgehog readout, not BMP.
- discussion_id: scube3_no_disease_specific_management_evidence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any SCUBE3-specific management, and does recombinant growth hormone
    help these patients?
  attaches_to:
  - treatments#
  rationale: >-
    The treatments section is empty on purpose. A PubMed search for SCUBE3 with
    growth hormone, treatment, or management returns no interventional study, no
    case series reporting a growth response, and no management guideline, and
    there is no GeneReviews chapter for this gene. Management is presumed
    symptomatic - orthopaedic care for the spine, dental care, growth monitoring
    - but nothing supports a treatment entry with a citation, so none is
    curated. The question is not idle: this disorder is reached through short
    stature clinics, where recombinant growth hormone is the default question,
    and the disease mechanism gives a reason to expect it to disappoint. The
    lesion is in the growth plate's response to BMP rather than in the
    GH-IGF-I axis, and the cohort that found SCUBE3 explicitly sorted it out of
    the GH-IGF-I subgroup. That is a mechanistic prediction, not a finding, and
    it is recorded here so it is not mistaken for one.
  evidence:
  - reference: PMID:38838658
    reference_title: "Genetic Findings in Short Turkish Children Born to Consanguineous Parents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions."
    explanation: >-
      Places SCUBE3 outside the GH-IGF-I axis group in the only cohort that
      sorted short-stature genes by that axis, which is the basis for the
      expectation stated above.
- discussion_id: scube3_phenotype_frequencies_not_quotable
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Should the majority-frequency phenotypes in the HPO annotation set for
    OMIM:619184 be curated, and from what citable source?
  attaches_to:
  - phenotypes#
  rationale: >-
    This entry curates ten phenotypes, and the four skeletal ones added most
    recently come from a single case report's radiology. That is a strange
    shape, and the reason is worth recording rather than leaving to be
    rediscovered. The deep-research reports carry a fuller list with HPO
    identifiers and denominators - brachydactyly and dental crowding at roughly
    80% (12/15), pointed chin ~85%, short palm ~80%, short long bone ~55%,
    enamel hypoplasia ~27%, and recurrent conductive hearing loss - all of which
    are more frequent than what is curated here. None was added, because the
    numbers come from HPO disease annotations rather than from a sentence in a
    reference this repository can cache, and the abstract of the discovery
    cohort (PMID:33308444) gives only the four domain headings. So the choice
    was between verifiable content and coverage, and this entry took
    verifiability. Closing this needs the full text of PMID:33308444, or the HPO
    annotation file treated as a citable source in its own right - which would
    also settle the cardiac and rib-number questions recorded separately here.
  notes: >-
    The absence of these phenotypes is a sourcing limit, not a claim that
    patients do not have them.
- discussion_id: scube3_cardiac_clause_unresolved
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Does the discovery cohort report atrial septal defect, and if so should this
    entry carry a cardiac phenotype?
  attaches_to:
  - disease#SCUBE3-Related Short Stature Syndrome
  rationale: >-
    The bound disease label ends "with or without cardiac anomalies", and this
    entry curates no cardiac phenotype. The reason is a cache limit, not a
    finding. The discovery cohort's abstract (PMID:33308444) lists reduced
    growth, skeletal features, craniofacial appearance and dental anomalies and
    no cardiac involvement, and its full text is not retrievable into
    references_cache, so nothing quotable exists either way. Two independent
    deep-research runs against different providers both report atrial septal
    defect in two of the cohort and patent foramen ovale in two, attributing it
    to HPO annotations on OMIM:619184; agreement between them is weak evidence
    because both are reading the same annotation set rather than the paper.
    Resolving this needs the full text of PMID:33308444 or the HPO annotation
    file cited as a source in its own right. Until then the phenotype is absent
    from this entry, and its absence should not be read as a negative finding.
  notes: >-
    Do not resolve this from a deep-research report. The claim needs a source
    whose exact sentence can be quoted and cached.
- discussion_id: scube3_tgf_beta_arm_contribution_unknown
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does loss of the SCUBE3 TGF-beta arm contribute to the human skeletal
    phenotype, or is the disease entirely a BMP deficit?
  attaches_to:
  - pathophysiology#Loss of SCUBE3 BMP Co-Receptor Function
  rationale: >-
    This entry models the disorder as a BMP co-receptor loss, which is what the
    disease literature demonstrates. SCUBE3 also has a separate, well
    characterized TGF-beta activity: its C-terminal CUB domain binds TGF-beta
    type II receptor directly and induces SMAD2/3 phosphorylation, so SCUBE3 is
    a ligand there rather than a co-receptor, and the downstream SMAD branch is
    a different one. That work was done in lung cancer cells, which is why it is
    a question here rather than a pathophysiology node - the same molecular
    interaction in a growth plate would be a different claim. Two observations
    keep it open. Recombinant SCUBE3 raises both BMP2 and TGF-beta in human
    bone-marrow mesenchymal stem cells and restores osteogenesis through SMAD
    phosphorylation, without the two branches being separated; and the
    SCUBE3-overexpressing transgenic mouse develops cardiac hypertrophy through
    TGF-beta1, showing the arm is active in vivo in a mammal. Nobody has asked
    which branch the skeletal phenotype needs.
  evidence:
  - reference: PMID:21441952
    reference_title: "SCUBE3 is an endogenous TGF-beta receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "bound to transforming growth factor-β (TGF-β) type II receptor through the C-terminal CUB domain, activated TGF-β signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation"
    explanation: >-
      Establishes the TGF-beta arm as a real biochemical activity of SCUBE3.
      Graded INDIRECT because it was shown in lung cancer cells: it supports the
      existence of the arm this question is about, not its operation in the
      growth plate.
  - reference: PMID:39250278
    reference_title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation"
    explanation: >-
      Both pathways move together in a skeletal cell type, and the study does
      not separate them. That is what leaves the question open rather than
      answering it.
- discussion_id: scube3_rib_number_not_explained_by_growth_plate_defect
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does SCUBE3 loss disturb somitogenesis, or is the reduced rib number a
    coincidental finding in one patient?
  attaches_to:
  - phenotypes#11 pairs of ribs
  - pathophysiology#Impaired BMP-Mediated Chondrogenesis and Osteogenesis
  rationale: >-
    Every other skeletal feature in this entry follows from defective
    endochondral bone growth, which acts on bones that already exist. Rib number
    does not: it is fixed by axial patterning during somitogenesis, well before
    the growth plate forms, so the curated mechanism does not reach it. Two
    readings are open. Either SCUBE3 has an earlier patterning role that nobody
    has looked for - BMP signalling does act in somite patterning, and mouse
    Scube3 is expressed in the cartilaginous condensations of ribs and vertebrae
    - or the finding is incidental. The second reading is the weaker one: a
    deep-research report puts eleven rib pairs at roughly 31% (4/13) of the
    cohort, which is recurrent rather than incidental, though that figure comes
    from HPO annotations and is not quotable in this entry. Settling it needs
    published rib counts across the reported cohort. Eleven rib pairs is also
    reported in SSFSC1, the BMP2-related disorder that shares this disease's
    naming series, which would fit a shared BMP-pathway patterning effect if it
    holds up.
  evidence:
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings"
    explanation: >-
      The single report of the finding this question is about.
  - reference: PMID:40331102
    reference_title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCUBE3 protein exhibits significant expression in various tissues, including primary osteoblasts, long bones, and the cartilage of the axial skeleton throughout development, while also playing a regulatory role in the FGF, Hedgehog, and TGF-β signaling pathways."
    explanation: >-
      Axial-skeleton cartilage expression throughout development is what makes
      an earlier patterning role worth asking about rather than dismissing.
references:
- reference: PMID:33308444
  title: "SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling."
- reference: PMID:37237303
  title: "The biology of SCUBE."
- reference: PMID:40331102
  title: "A Novel Homozygous Missense SCUBE3 Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 2."
- reference: PMID:34142127
  title: "Saturation mutagenesis defines novel mouse models of severe spine deformity."
- reference: PMID:39250278
  title: "SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-beta signaling pathway."
- reference: PMID:37189178
  title: "Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration."
- reference: PMID:40912446
  title: "Redundant and novel functions of scube genes during zebrafish development."
- reference: PMID:38838658
  title: "Genetic Findings in Short Turkish Children Born to Consanguineous Parents."
- reference: PMID:39706863
  title: "Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia."
- reference: PMID:27815347
  title: "The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations."
- reference: PMID:21441952
  title: "SCUBE3 is an endogenous TGF-beta receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer."

📚

References & Deep Research

References

11

PMID:33308444

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.