Acromesomelic Dysplasia PRKG2 Type

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Recessive HP:0000007

AMDP results from biallelic PRKG2 loss of function. Reported families are consanguineous with homozygous variants, and heterozygous parents and siblings are unaffected.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:37789084 SUPPORT Human Clinical

"Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia"

States the recessive mode of inheritance for the entity.

PMID:34782440 SUPPORT Human Clinical

"four individuals from two independent families were identified harbouring homozygous frameshift or stop-gain variants in PRKG2"

Independent families carry homozygous biallelic variants, consistent with recessive inheritance.

PMID:41574272 SUPPORT Human Clinical

"we identified two novel compound-heterozygous variants in the PRKG2 gene"

Compound heterozygosity outside a consanguineous setting confirms that two damaged alleles, not homozygosity as such, are what is required.

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Mechanistic Hypotheses

3

c-Raf-1 Ser43 MAPK-Brake Model

raf1_mapk_brake_model CANONICAL

Evidence balance 2 support

cGKII restrains the FGF-driven MAPK cascade in growth-plate chondrocytes by phosphorylating c-Raf-1 at Ser43, and pathogenic alleles lose that phosphorylation and with it the regulation it provides. The model is about the missing brake; it does not by itself specify how far ERK1/2 output moves in a growth plate. This is the canonical model for AMDP because it is the readout against which every human PRKG2 allele has been assayed: the founding nonsense and frameshift alleles, the p.Asp761Glufs*34 allele from an independent family, and the first missense allele p.Val470Gly all fail the same Raf-1/ERK test. It also connects AMDP to the wider growth-plate literature, where excess FGFR3-MAPK signalling is the established cause of achondroplasia and where CNP-cGMP is the physiological counterweight.

Pathograph links

Loss of cGKII Kinase Activity Downstream of CNP/NPR-B -> Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade DIRECT Wild-type cGKII phosphorylates c-Raf-1 at Ser43 to damp FGF-driven MAPK output. Mutant cGKII does not perform that phosphorylation, so the regulatory input is lost. What the assays measure is the loss of regulation; how far chondrocyte ERK output actually moves as a result has not been quantified.

Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade -> Dysregulated SOX9-Dependent Chondrocyte Collagen Program DIRECT The altered MAPK output feeds directly into the SOX9-controlled collagen transcriptional program of the growth-plate chondrocyte.

Show evidence (2 references)

PMID:33106379 SUPPORT In Vitro

"alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2"

The founding human study establishes the Raf-1/ERK readout for AMDP alleles.

PMID:37789084 SUPPORT In Vitro

"functional studies of the novel missense variant, p.Val470Gly, revealed that it was unable to down-regulate FGF2-induced MAPK signaling and, thus, would be predicted to cause growth delay"

An independent allele class reproduces the same failure, which is what makes this the canonical model. This is also the one source that states the direction unambiguously - the mutant is unable to down-regulate MAPK signalling - where the other two abstracts phrase it in a way that reads both ways.

SOX9 Nuclear-Exclusion Switch Model

sox9_nuclear_exclusion_switch ALTERNATIVE

Evidence balance 2 support

cGKII acts as the switch that ends proliferation and starts hypertrophic differentiation by excluding SOX9 from the chondrocyte nucleus; without it, SOX9 persists and cells accumulate in a postmitotic but non-hypertrophic state. The model rests on the cGKII-deficient KMI rat, where SOX9 knockdown rescues the differentiation block, and it is attractive for AMDP because it predicts exactly the collagen shift measured in the human alleles: SOX9 drives COL2A1 and represses COL10A1, and the human mutants upregulate COL2A1 while downregulating COL10A1. It is curated as ALTERNATIVE rather than canonical because no human AMDP allele has been tested for SOX9 localisation.

Pathograph links

Loss of cGKII Kinase Activity Downstream of CNP/NPR-B -> Persistent Nuclear SOX9 in Postmitotic Chondrocytes DIRECT In the alternative model, the substrate that matters is SOX9 rather than c-Raf-1: cGKII normally blocks SOX9 nuclear entry, so losing the kinase leaves SOX9 in the nucleus.

Persistent Nuclear SOX9 in Postmitotic Chondrocytes -> Dysregulated SOX9-Dependent Chondrocyte Collagen Program DIRECT Retained nuclear SOX9 directly sustains its own transcriptional program, holding COL2A1 high and COL10A1 low.

Show evidence (2 references)

PMID:15466490 SUPPORT Model Organism

"a novel role of cGKII as a molecular switch, coupling the cessation of proliferation and the start of hypertrophic differentiation of chondrocytes through attenuation of Sox9 function"

States the model in full, in the naturally occurring rat cGKII mutant.

PMID:33106379 SUPPORT In Vitro

"They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9."

The human alleles produce a SOX9-dependent collagen shift in the direction this model predicts, which is suggestive but does not localise SOX9.

GSK-3beta / beta-Catenin Hypertrophy Route

gsk3b_beta_catenin_route ALTERNATIVE

Evidence balance 2 support

cGKII phosphorylates and inactivates GSK-3beta, sparing beta-catenin and permitting the canonical Wnt output that drives chondrocyte hypertrophy. This is the only one of the three models tested by genetic epistasis in a mammal: removing one Gsk3b allele partially rescues the Prkg2-null growth plate. The rescue is partial, which is itself the argument that GSK-3beta is one route rather than the whole mechanism, and no human AMDP data address it.

The three groups are not mutually exclusive. A single kinase with several substrates can act through all of them at once, and the growth-plate phenotypes they predict overlap. What separates them for curation purposes is which has been tested in human AMDP alleles, which is only the first.

Pathograph links

Loss of cGKII Kinase Activity Downstream of CNP/NPR-B -> Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling DIRECT In the third model the critical substrate is GSK-3beta, which cGKII phosphorylates and thereby inactivates.

Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling -> Impaired Endochondral Longitudinal Bone Growth INDIRECT KNOWN INTERMEDIATES Reduced beta-catenin-dependent hypertrophic differentiation lengthens the growth plate and slows the conversion of cartilage into bone.

Show evidence (2 references)

PMID:18551195 SUPPORT Model Organism

"These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII."

States the model's central claim.

PMID:18551195 SUPPORT Model Organism

"were partially rescued by haploinsufficiency of Gsk3b"

The rescue is explicitly partial, which is why this is curated as one contributing route rather than as the canonical mechanism.

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Discussions and Knowledge Gaps

4

Would vosoritide, which acts upstream of cGKII, be expected to fail in AMDP where it succeeds in NPR2 deficiency?

KNOWLEDGE GAP OPEN cnp_axis_pharmacology_in_amdp

Attached to

treatments# pathophysiology#Loss of cGKII Kinase Activity Downstream of CNP/NPR-B

Vosoritide raises CNP signalling through NPR-B, which sits upstream of cGKII. A 2026 phase 2 basket trial reported a marked growth-velocity gain in children with heterozygous NPR2 variants, so the axis is pharmacologically tractable where receptor signalling is merely reduced. AMDP is the harder case in principle: the receptor is intact and it is the intracellular effector that is absent, so there may be nothing left to transduce the agonised signal. The mouse epistasis result points the same way, since growth-plate CNP overexpression fails to rescue the Prkg2-null skeleton. Against that, the human AMDP alleles are not all complete nulls and residual cGKII might be drivable. No treatment data of any kind have been published for AMDP, so this entry carries no treatments section rather than an inferred one. The `treatments: []` section is deliberately empty and present rather than absent, so that the absence of published management is a curated statement rather than an omission.

Show evidence (2 references)

PMID:41967490 SUPPORT Human Clinical

"Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN, and NPR2 deficiency"

Establishes that CNP-analogue therapy works in a related axis disorder. Support is partial because the trial enrolled heterozygous NPR2 carriers, not AMDP or biallelic NPR2 disease.

PMID:12193576 SUPPORT Model Organism

"targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice"

The mouse null is the closest available test of upstream agonism against cGKII loss, and it fails; support is partial because a complete mouse null may be a harsher test than a human hypomorphic genotype.

Which cGKII substrate route carries the human AMDP phenotype, and in what proportion?

KNOWLEDGE GAP OPEN prkg2_downstream_route_arbitration

Attached to

mechanistic_hypotheses#raf1_mapk_brake_model mechanistic_hypotheses#sox9_nuclear_exclusion_switch mechanistic_hypotheses#gsk3b_beta_catenin_route

Three routes have been proposed from the same kinase - c-Raf-1 Ser43 with MAPK restraint, SOX9 nuclear exclusion, and GSK-3beta inactivation with beta-catenin accumulation - each established in a different system, and none excludes the others. Only the first has been assayed against human AMDP alleles, and it was chosen as the assay largely because it was already the published readout rather than because it was shown to dominate. A single patient-derived chondrocyte or iPSC model measuring all three readouts on the same alleles would arbitrate this; the iPSC line already exists for one AMDP proband, so the experiment is tractable.

Proposed experiments

Parallel three-readout assay of AMDP alleles in a chondrogenic model

amdp_three_readout_arbitration

Express the reported AMDP alleles, spanning truncating, splice and missense classes, in a chondrogenic system and measure FGF2-induced ERK1/2 phosphorylation, SOX9 nuclear localisation, and GSK-3beta phosphorylation with beta-catenin levels on the same samples, so the three proposed routes are compared rather than assumed.

Would support

pathophysiology#Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade pathophysiology#Persistent Nuclear SOX9 in Postmitotic Chondrocytes pathophysiology#Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling

Supporting outcome

One readout is disturbed across all allele classes while the others track it only weakly, identifying the dominant route.
All three readouts move together across allele classes, supporting a genuinely multi-substrate mechanism rather than a single dominant route.

Refuting outcome

Allele severity in patients fails to correlate with any of the three readouts, indicating that the operative cGKII substrate in the human growth plate has not yet been identified.

Does residual cGKII activity set AMDP severity, as residual signalling does across the GDF5-BMPR1B acromesomelic dysplasias?

KNOWLEDGE GAP OPEN prkg2_residual_activity_and_severity

Attached to

pathophysiology#Loss of cGKII Kinase Activity Downstream of CNP/NPR-B genetic#Biallelic PRKG2 Loss-of-Function Variants

A 2025 report attributes an attenuated phenotype to partial rather than complete loss of protein function, which is the same dose-response logic that separates du Pan syndrome from Grebe dysplasia in the other half of ISDS group 16. It is stated there as a hypothesis on one proband, and the reported PRKG2 families range from spondylometaphyseal dysplasia with no acromesomelic shortening to severe acromesomelic disease without a measured activity series to explain the spread. A systematic comparison of residual kinase activity against phenotype has not been done.

Show evidence (1 reference)

PMID:41574272 SUPPORT Human Clinical

"We hypothesize that these alterations cause a partial, rather than a complete, loss of protein function, which may account for the patient's attenuated clinical phenotype."

The dose-response account is offered as a hypothesis about a single proband, which is what makes this an open question rather than a curated mechanism.

By how much, and in which direction, does chondrocyte ERK1/2 output actually move when cGKII is lost?

KNOWLEDGE GAP OPEN mapk_defect_direction_in_growth_plate

Attached to

pathophysiology#Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade

That cGKII restraint on the cascade is lost is established: mutant protein does not phosphorylate c-Raf-1 at Ser43, and one allele is reported as unable to down-regulate FGF2-induced MAPK signalling. What is not established is the magnitude or even the sign of the resulting change in a growth plate. The published assays are transfection experiments in HEK293T cells, and the abstract wording in two of the three reports is ambiguous between the mutant reducing ERK activation and the mutant failing to reduce it, which is a real hazard for anyone reading these entries against the sources. This entry therefore annotates the cascade ABNORMAL and its negative regulation DECREASED, names the node for the lesion, and leaves the output direction open. Measuring phospho-ERK in patient-derived or Prkg2-null growth-plate chondrocytes would close it.

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Pathophysiology

7

Biallelic PRKG2 Loss of Function

Pathogenic variants on both PRKG2 alleles eliminate or cripple cGMP-dependent protein kinase II. Truncating transcripts are degraded by nonsense-mediated decay, and residual mutant protein is present at markedly reduced levels and lacks all or part of the catalytic kinase domain.

PRKG2 hgnc:9416

Nonsense-mediated decay of PRKG2 transcripts GO:0000184 ↑ INCREASED

Downstream

Loss of cGKII Kinase Activity Downstream of CNP/NPR-B Absent or truncated cGKII directly removes the cGMP-activated kinase activity that transduces the CNP/NPR-B signal inside the chondrocyte.

Show evidence (2 references)

PMID:33106379 SUPPORT Human Clinical

"Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain"

Establishes biallelic PRKG2 loss of function as the initiating lesion.

PMID:34782440 SUPPORT In Vitro

"For both variants, cGKII was detected at the predicted size (figure 1C), although at dramatically reduced levels (>=80%) compared with the wild type"

Immunoblotting quantifies the loss of cGKII protein produced by two independent truncating alleles.

Loss of cGKII Kinase Activity Downstream of CNP/NPR-B

cGKII is the cGMP-activated kinase that carries the CNP/NPR-B growth signal forward inside growth-plate chondrocytes. This node is the mechanistic junction with acromesomelic dysplasia Maroteaux type: NPR2 variants disable the receptor that generates cGMP, PRKG2 variants disable the kinase that reads it, and the two disorders converge on the same downstream defect.

c-Raf-1 Ser43 MAPK-Brake Model GSK-3beta / beta-Catenin Hypertrophy Route SOX9 Nuclear-Exclusion Switch Model

Growth-plate chondrocyte CL:0000138 Growth-plate cartilage chondrocyte CL:1000217

Protein phosphorylation GO:0006468 ↓ DECREASED Intracellular signal transduction GO:0035556 ↓ DECREASED

cGMP-dependent protein kinase activity GO:0004692 ⇓ LOSS OF FUNCTION cGMP binding GO:0030553 ⇓ LOSS OF FUNCTION

Animal models

Prkg2-null mouse Mouse recapitulates A complete genetic null of the same gene, giving the cleanest available readout of what losing cGKII does to the growth plate.

Downstream

Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade Wild-type cGKII phosphorylates c-Raf-1 at Ser43 to damp FGF-driven MAPK output. Mutant cGKII does not perform that phosphorylation, so the regulatory input is lost. What the assays measure is the loss of regulation; how far chondrocyte ERK output actually moves as a result has not been quantified.

Persistent Nuclear SOX9 in Postmitotic Chondrocytes In the alternative model, the substrate that matters is SOX9 rather than c-Raf-1: cGKII normally blocks SOX9 nuclear entry, so losing the kinase leaves SOX9 in the nucleus.

Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling In the third model the critical substrate is GSK-3beta, which cGKII phosphorylates and thereby inactivates.

Show evidence (2 references)

PMID:33106379 SUPPORT Human Clinical

"C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and..."

Establishes cGKII as the downstream mediator of the CNP/NPR-B axis in chondrogenesis and bone growth.

PMID:12193576 SUPPORT Model Organism

"Here we show that targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice."

Genetic epistasis places cGKII strictly downstream of CNP: supplying the ligand cannot compensate for loss of the kinase, which is why this node, not cGMP production, is where the AMDP lesion sits.

Persistent Nuclear SOX9 in Postmitotic Chondrocytes

SOX9 sustains the proliferative and matrix-producing chondrocyte state and represses hypertrophic differentiation. cGKII normally excludes SOX9 from the nucleus at the point where chondrocytes stop dividing, and without that exclusion SOX9 activity persists in postmitotic cells, which stall before hypertrophy. This is the mechanism established in the cGKII-deficient KMI rat; whether it operates in human AMDP has not been tested.

SOX9 Nuclear-Exclusion Switch Model

Growth-plate cartilage chondrocyte CL:1000217

Negative regulation of protein import into nucleus GO:0042308 ↓ DECREASED Chondrocyte hypertrophy GO:0003415 ↓ DECREASED

Animal models

Komeda miniature rat Ishikawa (KMI) Rat recapitulates The KMI growth plate shows the retained nuclear SOX9 and the differentiation arrest that define this node, and SOX9 knockdown rescues the arrest ex vivo.

Downstream

Dysregulated SOX9-Dependent Chondrocyte Collagen Program Retained nuclear SOX9 directly sustains its own transcriptional program, holding COL2A1 high and COL10A1 low.

Show evidence (2 references)

PMID:15466490 SUPPORT Model Organism

"The expression of Sox9, an inhibitory regulator of hypertrophic differentiation, persisted in the nuclei of postmitotic chondrocytes of the KMI growth plate."

Documents persistent nuclear SOX9 in the cGKII-deficient growth plate.

PMID:15466490 SUPPORT Model Organism

"The impaired differentiation of cultured KMI chondrocytes was restored by the silencing of Sox9 through RNA interference."

Knocking SOX9 down rescues the differentiation block, which is the epistasis result that makes SOX9 causal rather than correlative here.

Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling

cGKII phosphorylates GSK-3beta and thereby inhibits it, which spares beta-catenin from degradation and permits canonical Wnt transcriptional output that drives chondrocyte hypertrophy. Without cGKII, GSK-3beta stays active and beta-catenin levels fall. The genetic test of this model is that removing one Gsk3b allele partially rescues the Prkg2-null growth plate.

GSK-3beta / beta-Catenin Hypertrophy Route

Growth-plate cartilage chondrocyte CL:1000217

Protein phosphorylation GO:0006468 ↓ DECREASED Canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

Animal models

Prkg2-null mouse Mouse recapitulates The same null is the system in which the GSK-3beta route was identified and tested by compound genetics.

Downstream

Impaired Endochondral Longitudinal Bone Growth Reduced beta-catenin-dependent hypertrophic differentiation lengthens the growth plate and slows the conversion of cartilage into bone.

Show evidence (2 references)

PMID:18551195 SUPPORT Model Organism

"We found that beta-catenin levels decreased in Prkg2(-/-) mice, while overexpression of cGKII increased the accumulation and transactivation function of beta-catenin in mouse chondroprogenitor ATDC5 cells."

Measures the beta-catenin consequence of losing cGKII in vivo and in vitro.

PMID:18551195 SUPPORT Model Organism

"Analyses of mice with compound deficiencies in both protein kinases (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b."

The compound-mutant rescue is the genetic evidence that GSK-3beta is on the causal path, and its partiality is why this is curated as one route among several rather than the whole mechanism.

Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade

In chondrocytes, cGKII acts as an inhibitory input onto the FGF-MAPK cascade by phosphorylating c-Raf-1 at Ser43. Losing that input dysregulates FGF2-driven ERK1/2 signalling in a pathway whose excess activity is a well-established cause of impaired chondrocyte proliferation in the FGFR3 chondrodysplasias. This node is deliberately named for the lesion rather than for a direction of change. Two of the three source abstracts phrase the mutant effect ambiguously - the clause reads equally as the mutant reducing ERK activation or as the mutant failing to reduce it - and only PMID:37789084 states it unambiguously, that the mutant was unable to down-regulate FGF2-induced MAPK signalling. Loss of restraint is therefore what the evidence supports; a quantified increase in chondrocyte ERK output is not.

c-Raf-1 Ser43 MAPK-Brake Model

Growth-plate chondrocyte CL:0000138

ERK1 and ERK2 cascade GO:0070371 ⚠ ABNORMAL Negative regulation of ERK1 and ERK2 cascade GO:0070373 ↓ DECREASED Fibroblast growth factor receptor signaling pathway GO:0008543 ⚠ ABNORMAL Peptidyl-serine phosphorylation of c-Raf-1 GO:0018105 ↓ DECREASED

Downstream

Dysregulated SOX9-Dependent Chondrocyte Collagen Program The altered MAPK output feeds directly into the SOX9-controlled collagen transcriptional program of the growth-plate chondrocyte.

Show evidence (4 references)

PMID:34782440 SUPPORT In Vitro

"Wild-type cGKII downregulated MAPK signalling by reducing ERK1/2 activation through the upstream phosphorylation of Raf-1 at Ser-43 in a cGMP-dependent manner."

Defines the normal inhibitory action of cGKII on the FGF-MAPK cascade that the disorder removes.

PMID:15869918 SUPPORT In Vitro

"CNP and 8-bromo-cGMP strongly and dose-dependently inhibited the induction of ERK phosphorylation by FGF2 and FGF18 without changing the level of FGFR-3"

Shows the CNP-cGMP arm restraining FGF-driven ERK activation in chondrocytes, the brake that PRKG2 loss removes.

PMID:15869918 SUPPORT In Vitro

"constitutes the negative cross talk between FGFs and the activity of MAPK"

Frames the relationship as reciprocal cross-talk, which is why this node is annotated as loss of a negative regulator rather than as a primary increase in FGF signalling.

+ 1 more reference

Dysregulated SOX9-Dependent Chondrocyte Collagen Program

COL10A1 marks hypertrophic chondrocytes and COL2A1 marks the proliferative and resting zones. Downregulation of COL10A1 with upregulation of COL2A1 indicates chondrocytes that fail to advance through hypertrophic maturation and remain in an earlier differentiation state.

Growth-plate chondrocyte CL:0000138 Hypertrophic chondrocyte CL:0000743

Chondrocyte differentiation GO:0002062 ⚠ ABNORMAL Chondrocyte hypertrophy GO:0003415 ↓ DECREASED Collagen biosynthetic process GO:0032964 ⚠ ABNORMAL Regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL Extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Animal models

Angus cattle PRKG2 R678X dwarfism Cattle recapitulates The bovine truncating allele reproduces the loss of PRKG2 control over COL2 and COL10 expression seen with the human alleles.

Downstream

Impaired Endochondral Longitudinal Bone Growth Chondrocytes that do not complete the proliferation-to-hypertrophy sequence directly reduce the rate of longitudinal growth generated at the physis.

Show evidence (3 references)

PMID:33106379 SUPPORT In Vitro

"They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9."

Directly documents the shifted collagen expression program in the mutant setting.

PMID:12193576 SUPPORT Model Organism

"CNP cannot increase the longitudinal bone growth, and chondrocytic proliferation and hypertrophy, and cartilage matrix synthesis in Prkg2(-/-) mice"

Cartilage matrix synthesis is measured alongside proliferation and hypertrophy as a cGKII-dependent output, which is the basis for annotating matrix and collagen processes on this node.

PMID:19887637 SUPPORT Model Organism

"These experiments indicate that the R678X mutation is functional, resulting in a loss of PRKG2 regulation of COL2 and COL10 mRNA expression."

A naturally occurring bovine PRKG2 nonsense allele independently shows loss of collagen-gene regulation. Evidence source is MODEL_ORGANISM because the measurement is in cattle.

Impaired Endochondral Longitudinal Bone Growth

Reduced longitudinal growth at the physis produces the disproportionate short stature, with the growth deficit falling most heavily on the middle and distal limb segments and accompanied by metaphyseal and vertebral change.

Growth-plate chondrocyte CL:0000138 Growth-plate cartilage chondrocyte CL:1000217

Endochondral bone growth GO:0003416 ↓ DECREASED Endochondral ossification GO:0001958 ↓ DECREASED Growth plate cartilage development GO:0003417 ⚠ ABNORMAL

Animal models

Dogo Argentino PRKG2 splice-site dwarfism Dog recapitulates A canine PRKG2 loss-of-function allele produces disproportionate dwarfism, supporting reduced longitudinal bone growth as the organism-level output of PRKG2 loss.

Show evidence (2 references)

PMID:33106379 SUPPORT Human Clinical

"Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones."

Documents the skeletal output of the growth deficit in the founding patients.

PMID:12193576 SUPPORT Model Organism

"The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral ossification"

The mouse null attributes the growth deficit specifically to impaired endochondral ossification.

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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

7

Limbs 4

Acromesomelic Limb Shortening Acromesomelia HP:0003086

Show evidence (1 reference)

PMID:33106379 SUPPORT Human Clinical

"two girls with severe short stature due to acromesomelic limb shortening"

The founding patients show the acromesomelic pattern.

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:36504352 SUPPORT Human Clinical

"moderate brachydactyly with cone-shaped epiphyses of the middle and proximal phalanges"

The sibling series documents brachydactyly with cone-shaped epiphyses.

Progressive Metaphyseal Alteration of the Long Bones Metaphyseal widening HP:0003016

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:33106379 SUPPORT Human Clinical

"mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones"

Establishes progressive metaphyseal change as part of the core phenotype.

Limited Elbow Extension HP:0001377

Show evidence (1 reference)

PMID:36504352 SUPPORT Human Clinical

"We detected biallelic novel variant (c.1635-1G > C) in PRKG2 in two brothers with mild to severe short stature, short limbs, cubitus varus, and brachydactyly."

Reports cubitus varus and, with the elbow limitation noted in the same series, restricted elbow movement.

Musculoskeletal 1

Platyspondyly with Anterior Vertebral Beaking HP:0000926

Show evidence (1 reference)

PMID:36504352 SUPPORT Human Clinical

"Radiological examination showed platyspondyly with anterior beaking of the vertebral bodies, stubby long bones with metaphyseal flaring"

Documents platyspondyly with anterior vertebral beaking in molecularly confirmed siblings.

Growth 1

Severe Disproportionate Short Stature Disproportionate short-limb short stature HP:0008873

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37789084 SUPPORT Human Clinical

"is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia"

States severe disproportionate short stature as a defining feature.

Other 1

Cone-Shaped Epiphyses Cone-shaped epiphysis HP:0010579

Show evidence (1 reference)

PMID:36504352 SUPPORT Human Clinical

"moderate brachydactyly with cone-shaped epiphyses of the middle and proximal phalanges"

Documents cone-shaped phalangeal epiphyses.

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Genetic Associations

1

Biallelic PRKG2 Loss-of-Function Variants (Causative)

Gene: PRKG2 hgnc:9416 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:33106379 SUPPORT Human Clinical

"Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain"

The founding study establishes the truncating allele class and its consequence for the kinase domain.

PMID:37789084 SUPPORT Human Clinical

"Here, we report the first missense variant and a second splice-site variant in PRKG2 in two patients with clinical and radiological features of acromesomelic dysplasia."

Extends the allelic spectrum beyond truncating variants to missense and splice-site alleles.

PMID:41574272 SUPPORT In Vitro

"Functional analysis unveiled a unique dual pathogenic mechanism: the missense variant creates a cryptic splice site, resulting in two aberrant protein products - an in-frame deletion and a missense substitution."

Shows that a PRKG2 missense change can act through splicing, so the coding consequence alone does not establish the allele's functional class.

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Diagnosis

1

Molecular Confirmation of Biallelic PRKG2 Variants

Diagnosis rests on identifying biallelic PRKG2 variants by exome or genome sequencing. Because the radiographic presentation overlaps AMDM and can resemble spondylometaphyseal dysplasia, PRKG2 is best reached through a broad skeletal-dysplasia panel or untargeted sequencing rather than a single-gene test.

Show evidence (1 reference)

PMID:34782440 SUPPORT Human Clinical

"In family 1, WGS and subsequent Sanger sequencing uncovered a homozygous pathogenic PRKG2 variant, NM_006259.3:c.2282dup (p.Asp761Glufs*34; online supplemental figure 1) in three brothers referred with spondylometaphyseal dysplasia"

Shows the diagnosis being made by genome sequencing in siblings whose referral diagnosis was a different radiographic category.

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Progression

2

Childhood

Age: Early childhood onward

Metaphyseal alteration of the long bones is described as progressively increasing rather than static, so a normal or near-normal early radiograph does not exclude the diagnosis.

Show evidence (1 reference)

PMID:33106379 SUPPORT Human Clinical

"Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones."

The founding series describes the metaphyseal changes as progressive.

Childhood to adulthood

Age: Age 5 to 20 years

Longitudinal follow-up of one sibling pair shows short stature worsening with age while the vertebral findings become less conspicuous, so spinal radiographs taken in adolescence may under-represent the earlier phenotype.

Show evidence (1 reference)

PMID:36504352 SUPPORT Human Clinical

"Annual follow-ups of the older brother from the age of 5 to 20 years revealed progression of short stature with age but platyspondyly and anterior beaking became less conspicuous."

The natural-history report documents divergent trajectories for stature and spinal findings.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population-based estimate exists. As of the 2024 mutational review only a handful of families had been reported, and the entity is described in the literature as extremely rare.

Show evidence (2 references)

PMID:37789084 SUPPORT Human Clinical

"Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia."

The mutational review characterises AMDP as extremely rare.

PMID:37789084 SUPPORT Human Clinical

"To date, only four variants have been reported; one nonsense, one splice-site, and two frameshifts in five AMDP families."

Quantifies the published case count behind the ultra-rare classification.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Acromesomelic Dysplasia PRKG2 Type:

Acromesomelic Dysplasia, Maroteaux Type MONDO:0011275

Overlapping Features The closest differential and the immediate upstream disorder in the same signalling axis: biallelic NPR2 variants disable the receptor that generates the cGMP signal cGKII transduces.

Distinguishing Features

Biallelic NPR2 variants rather than biallelic PRKG2 variants establish AMDM.
Pronounced generalised cone-shaped epiphyses with phalangeal shortening are characteristic of AMDM; in the PRKG2 family presenting as spondylometaphyseal dysplasia, coning was subtle and unaccompanied by shortening.

Show evidence (2 references)

PMID:33106379 SUPPORT Human Clinical

"In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes."

Identifies the upstream NPR2 disorder that AMDP most closely resembles.

PMID:34782440 SUPPORT Human Clinical

"The metaphyses of the distal phalanges were somewhat cone-shaped in one child, but not pronounced, generalised or associated with shortening, as seen in AMDM."

Gives the radiographic contrast between this PRKG2 family and AMDM.

Spondylometaphyseal Dysplasia

Overlapping Features One PRKG2 family was referred with spondylometaphyseal dysplasia and had no acromesomelic shortening, so PRKG2 belongs in the differential of that radiographic category as well as of acromesomelic dysplasia.

Distinguishing Features

Long slender femoral necks with platyspondyly and anterior vertebral body projections, without acromesomelic shortening, was the presenting pattern in the PRKG2 family reported by the 100,000 Genomes Project.

Show evidence (1 reference)

PMID:34782440 SUPPORT Human Clinical

"In summary, family 1 exhibited a skeletal phenotype characterised by spondylometaphyseal dysplasia, rather than acromesomelic dysplasia as expected in AMDP and AMDM."

Documents the spondylometaphyseal presentation of biallelic PRKG2 loss.

🐁

Animal Models

4

Prkg2-null mouse

The engineered cGKII-null mouse is the reference genetic model. It is dwarfed with an elongated growth plate and impaired chondrocyte hypertrophy, and it is the model in which cGKII was placed downstream of CNP by showing that growth-plate CNP overexpression fails to rescue it.

Species

Mouse

Genotype

Prkg2 knockout (homozygous null)

Genes

PRKG2 hgnc:9416

Publication

PMID:12193576

Pathograph links

Loss of cGKII Kinase Activity Downstream of CNP/NPR-B recapitulates fidelity: high A complete genetic null of the same gene, giving the cleanest available readout of what losing cGKII does to the growth plate.

Limitations: Human AMDP alleles are mostly truncating but not always complete nulls, and mouse growth-plate proportions do not reproduce the human acromesomelic distribution of shortening.

Readouts

Rescue of skeletal defect by growth-plate CNP overexpression

Direction: UNCHANGED

Interpretation: Supplying the upstream ligand does not correct the phenotype, placing the lesion downstream of CNP and cGMP production. This is the negative result that makes the epistasis argument.

Show evidence (1 reference)

PMID:12193576 SUPPORT Model Organism

"targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice"

Reports the rescue failure directly.

Show evidence (1 reference)

PMID:12193576 SUPPORT Model Organism

"This study provides in vivo and in vitro genetic evidence that cGKII plays a critical role in CNP-mediated endochondral ossification."

Supports treating the mouse null as informative for the cGKII node.

Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling recapitulates fidelity: moderate The same null is the system in which the GSK-3beta route was identified and tested by compound genetics.

Limitations: The Gsk3b haploinsufficiency rescue is partial, so the model demonstrates that this route contributes without establishing how much of the phenotype it carries; nothing equivalent has been measured in human AMDP.

Readouts

Growth plate length and chondrocyte hypertrophy under Gsk3b haploinsufficiency

Direction: RESTORED

Interpretation: Partial correction of the elongated growth plate when one Gsk3b allele is removed, the genetic test that puts GSK-3beta on the causal path.

Show evidence (1 reference)

PMID:18551195 SUPPORT Model Organism

"the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b"

Reports the compound-mutant rescue and its partiality.

Show evidence (1 reference)

PMID:18551195 SUPPORT Model Organism

"in mice, cGKII deficiency results in dwarfism"

Establishes the mouse null as a growth-phenotype model of cGKII loss.

Komeda miniature rat Ishikawa (KMI)

A naturally occurring recessive cGKII deletion in the rat, with longitudinal growth retardation and an expanded growth plate packed with postmitotic but non-hypertrophic chondrocytes. It is the system in which the SOX9 nuclear-exclusion model was established.

Species

Rat

Genotype

Prkg2 (mri) deletion, homozygous

Genes

PRKG2 hgnc:9416

Publication

PMID:15466490

Pathograph links

Persistent Nuclear SOX9 in Postmitotic Chondrocytes recapitulates fidelity: moderate The KMI growth plate shows the retained nuclear SOX9 and the differentiation arrest that define this node, and SOX9 knockdown rescues the arrest ex vivo.

Limitations: The SOX9 localisation result comes entirely from rat tissue and cultured rat chondrocytes; no human AMDP allele has been tested for it, which is why the node it supports is curated under an ALTERNATIVE hypothesis group.

Readouts

Nuclear SOX9 in postmitotic growth-plate chondrocytes

Direction: INCREASED

Interpretation: SOX9 that should have been cleared from the nucleus at the end of proliferation is still present, marking the differentiation arrest.

Show evidence (1 reference)

PMID:15466490 SUPPORT Model Organism

"The expression of Sox9, an inhibitory regulator of hypertrophic differentiation, persisted in the nuclei of postmitotic chondrocytes of the KMI growth plate."

Reports the localisation measurement in affected animals.

Show evidence (1 reference)

PMID:15466490 SUPPORT Model Organism

"KMIs showed an expanded growth plate and impaired bone healing with abnormal accumulation of postmitotic but nonhypertrophic chondrocytes."

Establishes the growth-plate phenotype that makes the rat informative for this node.

Angus cattle PRKG2 R678X dwarfism

A naturally occurring nonsense PRKG2 allele segregating in American Angus cattle causes disproportionate dwarfism and was the first evidence that PRKG2 loss impairs longitudinal growth in a large mammal.

Species

Cattle

Genotype

PRKG2 p.Arg678* (R678X) homozygous

Genes

PRKG2 hgnc:9416

Publication

PMID:19887637

Pathograph links

Dysregulated SOX9-Dependent Chondrocyte Collagen Program recapitulates fidelity: moderate The bovine truncating allele reproduces the loss of PRKG2 control over COL2 and COL10 expression seen with the human alleles.

Limitations: Bovine growth-plate biology and body proportions differ from human, and the cattle phenotype is described as dwarfism without the acromesomelic radiographic detail used to define the human entity. The direction of the collagen change also diverges: dwarf cattle show COL10 mRNA increased, whereas the human alleles downregulate COL10A1. What the two systems agree on is that PRKG2 loss removes regulation of the collagen genes, not which way each transcript moves, so the model supports the regulatory claim at this node and not the human direction of effect.

Readouts

COL2 and COL10 mRNA expression

Direction: INCREASED

Interpretation: Loss of PRKG2 regulation raises collagen transcript levels in dwarf cattle, the same regulatory node dysregulated by the human alleles.

Show evidence (1 reference)

PMID:19887637 SUPPORT Model Organism

"COL2 and COL10 mRNA expression was increased in dwarf cattle compared with unaffected cattle."

Reports the direct transcript measurement in affected animals.

Show evidence (1 reference)

PMID:19887637 SUPPORT Model Organism

"These experiments indicate that the R678X mutation is functional, resulting in a loss of PRKG2 regulation of COL2 and COL10 mRNA expression."

Supports treating the bovine allele as informative for the collagen-program node.

Dogo Argentino PRKG2 splice-site dwarfism

Two Dogo Argentino dogs with disproportionate dwarfism were homozygous for a PRKG2 splice-donor variant that segregated with the phenotype in a nine-animal family, a canine counterpart of the human splice-site alleles.

Species

Dog

Genotype

PRKG2 c.1634+1G>T homozygous

Genes

PRKG2 hgnc:9416

Publication

PMID:34680883

Pathograph links

Impaired Endochondral Longitudinal Bone Growth recapitulates fidelity: moderate A canine PRKG2 loss-of-function allele produces disproportionate dwarfism, supporting reduced longitudinal bone growth as the organism-level output of PRKG2 loss.

Limitations: The dogs were characterised clinically and genomically rather than histologically, so the growth-plate lesion itself was not measured, and canine breed conformation confounds proportionality assessment.

Show evidence (1 reference)

PMID:34680883 SUPPORT Model Organism

"The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs."

Segregation in a nine-animal family supports the allele as causal for the growth phenotype.

{ }

Source YAML

click to show

name: Acromesomelic Dysplasia PRKG2 Type
synonyms:
- AMDP
- Acromesomelic dysplasia 4
- Acromesomelic dysplasia, PRKG2-related
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Acromesomelic dysplasia, PRKG2 type (AMDP) is an ultra-rare autosomal
  recessive skeletal dysplasia caused by biallelic loss-of-function variants in
  PRKG2, which encodes cGMP-dependent protein kinase II (cGKII). cGKII is the
  intracellular effector immediately downstream of the C-type natriuretic
  peptide (CNP) / natriuretic peptide receptor-B (NPR-B) axis whose upstream
  receptor, NPR2, is mutated in acromesomelic dysplasia Maroteaux type. Loss of
  cGKII removes an inhibitory brake on fibroblast growth factor signaling in
  growth-plate chondrocytes: the mutant kinase fails to phosphorylate c-Raf-1 at
  Ser43, so FGF2-induced ERK1/2 activation is no longer restrained, and the
  SOX9-dependent chondrocyte collagen program is dysregulated with COL10A1
  downregulation and COL2A1 upregulation. The clinical result is severe
  disproportionate short stature with acromesomelic limb shortening,
  brachydactyly, mild to moderate platyspondyly with anterior vertebral beaking,
  and progressive metaphyseal alteration of the long bones. The phenotype is
  variable: one reported family presented as spondylometaphyseal dysplasia with
  no acromesomelic shortening at all, so PRKG2 should be considered across a
  wider radiographic range than the entity name suggests.
disease_term:
  preferred_term: acromesomelic dysplasia, PRKG2 type
  term:
    id: MONDO:0030553
    label: acromesomelic dysplasia 4
parents:
- Skeletal Dysplasia
classifications:
  isds_skeletal_category:
  - classification_value: acromesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 16 "Acromesomelic dysplasias"; listed as the
      PRKG2-linked acromesomelic dysplasia type (OMIM 619636). This entity was
      first reported in 2020 and so appears in the 2023 revision but not in the
      2019 revision (PMID:31633310), which is why no 2019 group is recorded here.
    evidence:
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        To date, four disease genes and seven distinct ACD subtypes with varying
        severity are recognised according to the 2023 revision of the nosology
        and classification of genetic skeletal disorders
      explanation: >-
        This is the sentence that ties the enumeration below to the 2023 ISDS
        nosology revision. It is quoted separately because the enumeration
        itself names diseases and OMIM numbers without repeating the nosology
        attribution, so on its own it would not support a group assignment.
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The remaining three ACD types encompass NPR2-linked Maroteaux type (OMIM
        #602875), the PRKG2-linked ACD type (OMIM #619636) and Osebold-Remondini
        type, which is not yet associated with a genomic locus (OMIM #112910).
      explanation: >-
        A 2024 report enumerating the seven acromesomelic chondrodysplasia types
        recognised by the 2023 nosology revision places the PRKG2-linked type
        inside that group.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. As of the 2024 mutational review only
    a handful of families had been reported, and the entity is described in the
    literature as extremely rare.
  evidence:
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely
      rare autosomal recessive skeletal dysplasia characterized by severe
      disproportionate short stature presenting with acromesomelia, mild
      metaphyseal widening of the long bones and mild spondylar dysplasia.
    explanation: The mutational review characterises AMDP as extremely rare.
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only four variants have been reported; one nonsense, one
      splice-site, and two frameshifts in five AMDP families.
    explanation: Quantifies the published case count behind the ultra-rare classification.
progression:
- phase: Childhood
  age_range: Early childhood onward
  notes: >-
    Metaphyseal alteration of the long bones is described as progressively
    increasing rather than static, so a normal or near-normal early radiograph
    does not exclude the diagnosis.
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing was performed in two girls with severe short stature due
      to acromesomelic limb shortening, brachydactyly, mild to moderate
      platyspondyly and progressively increasing metaphyseal alterations of the
      long bones.
    explanation: The founding series describes the metaphyseal changes as progressive.
- phase: Childhood to adulthood
  age_range: Age 5 to 20 years
  notes: >-
    Longitudinal follow-up of one sibling pair shows short stature worsening
    with age while the vertebral findings become less conspicuous, so spinal
    radiographs taken in adolescence may under-represent the earlier phenotype.
  evidence:
  - reference: PMID:36504352
    reference_title: Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Annual follow-ups of the older brother from the age of 5 to 20 years
      revealed progression of short stature with age but platyspondyly and
      anterior beaking became less conspicuous.
    explanation: The natural-history report documents divergent trajectories for stature and spinal findings.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    AMDP results from biallelic PRKG2 loss of function. Reported families are
    consanguineous with homozygous variants, and heterozygous parents and
    siblings are unaffected.
  evidence:
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely
      rare autosomal recessive skeletal dysplasia
    explanation: States the recessive mode of inheritance for the entity.
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four individuals from two independent families were identified harbouring
      homozygous frameshift or stop-gain variants in PRKG2
    explanation: Independent families carry homozygous biallelic variants, consistent with recessive inheritance.
  - reference: PMID:41574272
    reference_title: "Case Report: Dual pathogenic mechanism of a PRKG2 missense variant underlies an attenuated phenotype of acromesomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two novel compound-heterozygous variants in the PRKG2 gene
    explanation: >-
      Compound heterozygosity outside a consanguineous setting confirms that two
      damaged alleles, not homozygosity as such, are what is required.
genetic:
- name: Biallelic PRKG2 Loss-of-Function Variants
  gene_term:
    preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported causative alleles include nonsense, frameshift, splice-site, and
    missense variants, in homozygous and in compound-heterozygous configuration.
    Most are loss of function: truncating transcripts are subject to
    nonsense-mediated decay and the residual mutant proteins partially or
    completely lack the kinase domain, and the first reported missense allele,
    p.Val470Gly, retains the protein but abolishes downstream signalling
    regulation. Allele class is not always readable from the coding change - the
    p.Asp544Tyr missense variant acts by creating a cryptic splice site and
    yields two aberrant products rather than a single substituted protein.
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous PRKG2 variants, a nonsense and a frameshift, were
      identified. The mutant transcripts are exposed to nonsense-mediated decay
      and the truncated mutant cGKII proteins, partially or completely lacking
      the kinase domain
    explanation: The founding study establishes the truncating allele class and its consequence for the kinase domain.
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the first missense variant and a second splice-site
      variant in PRKG2 in two patients with clinical and radiological features
      of acromesomelic dysplasia.
    explanation: Extends the allelic spectrum beyond truncating variants to missense and splice-site alleles.
  - reference: PMID:41574272
    reference_title: "Case Report: Dual pathogenic mechanism of a PRKG2 missense variant underlies an attenuated phenotype of acromesomelic dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis unveiled a unique dual pathogenic mechanism: the
      missense variant creates a cryptic splice site, resulting in two aberrant
      protein products - an in-frame deletion and a missense substitution.
    explanation: >-
      Shows that a PRKG2 missense change can act through splicing, so the coding
      consequence alone does not establish the allele's functional class.
pathophysiology:
- name: Biallelic PRKG2 Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Pathogenic variants on both PRKG2 alleles eliminate or cripple cGMP-dependent
    protein kinase II. Truncating transcripts are degraded by nonsense-mediated
    decay, and residual mutant protein is present at markedly reduced levels and
    lacks all or part of the catalytic kinase domain.
  genes:
  - preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  biological_processes:
  - preferred_term: Nonsense-mediated decay of PRKG2 transcripts
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous PRKG2 variants, a nonsense and a frameshift, were
      identified. The mutant transcripts are exposed to nonsense-mediated decay
      and the truncated mutant cGKII proteins, partially or completely lacking
      the kinase domain
    explanation: Establishes biallelic PRKG2 loss of function as the initiating lesion.
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      For both variants, cGKII was detected at the predicted size (figure 1C),
      although at dramatically reduced levels (>=80%) compared with the wild type
    explanation: Immunoblotting quantifies the loss of cGKII protein produced by two independent truncating alleles.
  downstream:
  - target: Loss of cGKII Kinase Activity Downstream of CNP/NPR-B
    causal_link_type: DIRECT
    description: >-
      Absent or truncated cGKII directly removes the cGMP-activated kinase
      activity that transduces the CNP/NPR-B signal inside the chondrocyte.
    evidence:
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PRKG2 encodes the cyclic guanosine monophosphate dependent protein
        kinase II (cGKII), which acts downstream of the natriuretic peptide
        receptor-B/C- natriuretic peptide (NPR-B/CNP).
      explanation: Places cGKII as the intracellular effector of the CNP/NPR-B axis whose activity the variants remove.
- name: Loss of cGKII Kinase Activity Downstream of CNP/NPR-B
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    cGKII is the cGMP-activated kinase that carries the CNP/NPR-B growth signal
    forward inside growth-plate chondrocytes. This node is the mechanistic
    junction with acromesomelic dysplasia Maroteaux type: NPR2 variants disable
    the receptor that generates cGMP, PRKG2 variants disable the kinase that
    reads it, and the two disorders converge on the same downstream defect.
  molecular_functions:
  - preferred_term: cGMP-dependent protein kinase activity
    term:
      id: GO:0004692
      label: cGMP-dependent protein kinase activity
    modifier: LOSS_OF_FUNCTION
  - preferred_term: cGMP binding
    term:
      id: GO:0030553
      label: cGMP binding
    modifier: LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: Protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: DECREASED
  - preferred_term: Intracellular signal transduction
    term:
      id: GO:0035556
      label: intracellular signal transduction
    modifier: DECREASED
  cell_types:
  - preferred_term: Growth-plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Growth-plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic
      peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic
      guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have
      been shown to play a pivotal role in chondrogenic differentiation and
      endochondral bone growth.
    explanation: Establishes cGKII as the downstream mediator of the CNP/NPR-B axis in chondrogenesis and bone growth.
  - reference: PMID:12193576
    reference_title: Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show that targeted expression of CNP in the growth plate
      chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice.
    explanation: >-
      Genetic epistasis places cGKII strictly downstream of CNP: supplying the
      ligand cannot compensate for loss of the kinase, which is why this node,
      not cGMP production, is where the AMDP lesion sits.
  downstream:
  - target: Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade
    causal_link_type: DIRECT
    hypothesis_groups:
    - raf1_mapk_brake_model
    description: >-
      Wild-type cGKII phosphorylates c-Raf-1 at Ser43 to damp FGF-driven MAPK
      output. Mutant cGKII does not perform that phosphorylation, so the
      regulatory input is lost. What the assays measure is the loss of
      regulation; how far chondrocyte ERK output actually moves as a result has
      not been quantified.
    evidence:
    - reference: PMID:33106379
      reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        alter the downstream mitogen activation protein kinase signalling
        pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently
        reduce ERK1/2 activation in response to fibroblast growth factor 2
      explanation: >-
        Functional assays show mutant cGKII cannot phosphorylate c-Raf-1 at
        Ser43, the step by which it normally regulates FGF2-induced ERK1/2
        signalling.
  - target: Persistent Nuclear SOX9 in Postmitotic Chondrocytes
    causal_link_type: DIRECT
    hypothesis_groups:
    - sox9_nuclear_exclusion_switch
    description: >-
      In the alternative model, the substrate that matters is SOX9 rather than
      c-Raf-1: cGKII normally blocks SOX9 nuclear entry, so losing the kinase
      leaves SOX9 in the nucleus.
    evidence:
    - reference: PMID:15466490
      reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This attenuation of Sox9 was due to the cGKII inhibition of nuclear
        entry of Sox9.
      explanation: Identifies SOX9 nuclear exclusion as the direct action of cGKII in this model.
  - target: Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling
    causal_link_type: DIRECT
    hypothesis_groups:
    - gsk3b_beta_catenin_route
    description: >-
      In the third model the critical substrate is GSK-3beta, which cGKII
      phosphorylates and thereby inactivates.
    evidence:
    - reference: PMID:18551195
      reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we performed a kinase substrate array and identified glycogen synthase
        kinase-3beta (GSK-3beta; encoded by Gsk3b) as a principal
        phosphorylation target of cGKII
      explanation: An unbiased substrate screen nominates GSK-3beta as a principal cGKII target.
- name: Persistent Nuclear SOX9 in Postmitotic Chondrocytes
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    SOX9 sustains the proliferative and matrix-producing chondrocyte state and
    represses hypertrophic differentiation. cGKII normally excludes SOX9 from
    the nucleus at the point where chondrocytes stop dividing, and without that
    exclusion SOX9 activity persists in postmitotic cells, which stall before
    hypertrophy. This is the mechanism established in the cGKII-deficient KMI
    rat; whether it operates in human AMDP has not been tested.
  cell_types:
  - preferred_term: Growth-plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Negative regulation of protein import into nucleus
    term:
      id: GO:0042308
      label: negative regulation of protein import into nucleus
    modifier: DECREASED
  - preferred_term: Chondrocyte hypertrophy
    term:
      id: GO:0003415
      label: chondrocyte hypertrophy
    modifier: DECREASED
  evidence:
  - reference: PMID:15466490
    reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The expression of Sox9, an inhibitory regulator of hypertrophic
      differentiation, persisted in the nuclei of postmitotic chondrocytes of
      the KMI growth plate.
    explanation: Documents persistent nuclear SOX9 in the cGKII-deficient growth plate.
  - reference: PMID:15466490
    reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The impaired differentiation of cultured KMI chondrocytes was restored by
      the silencing of Sox9 through RNA interference.
    explanation: >-
      Knocking SOX9 down rescues the differentiation block, which is the
      epistasis result that makes SOX9 causal rather than correlative here.
  downstream:
  - target: Dysregulated SOX9-Dependent Chondrocyte Collagen Program
    causal_link_type: DIRECT
    hypothesis_groups:
    - sox9_nuclear_exclusion_switch
    description: >-
      Retained nuclear SOX9 directly sustains its own transcriptional program,
      holding COL2A1 high and COL10A1 low.
    evidence:
    - reference: PMID:15466490
      reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        cGKII attenuated the Sox9 functions to induce the chondrogenic
        differentiation and to inhibit the hypertrophic differentiation of
        chondrocytes
      explanation: States the two transcriptional outputs of SOX9 that cGKII normally restrains.
- name: Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    cGKII phosphorylates GSK-3beta and thereby inhibits it, which spares
    beta-catenin from degradation and permits canonical Wnt transcriptional
    output that drives chondrocyte hypertrophy. Without cGKII, GSK-3beta stays
    active and beta-catenin levels fall. The genetic test of this model is that
    removing one Gsk3b allele partially rescues the Prkg2-null growth plate.
  cell_types:
  - preferred_term: Growth-plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: DECREASED
  - preferred_term: Canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:18551195
    reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that beta-catenin levels decreased in Prkg2(-/-) mice, while
      overexpression of cGKII increased the accumulation and transactivation
      function of beta-catenin in mouse chondroprogenitor ATDC5 cells.
    explanation: Measures the beta-catenin consequence of losing cGKII in vivo and in vitro.
  - reference: PMID:18551195
    reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Analyses of mice with compound deficiencies in both protein kinases
      (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and
      elongated growth plate associated with cGKII deficiency were partially
      rescued by haploinsufficiency of Gsk3b.
    explanation: >-
      The compound-mutant rescue is the genetic evidence that GSK-3beta is on
      the causal path, and its partiality is why this is curated as one route
      among several rather than the whole mechanism.
  downstream:
  - target: Impaired Endochondral Longitudinal Bone Growth
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - gsk3b_beta_catenin_route
    description: >-
      Reduced beta-catenin-dependent hypertrophic differentiation lengthens the
      growth plate and slows the conversion of cartilage into bone.
    evidence:
    - reference: PMID:18551195
      reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we determined that this growth defect was a consequence of an elongated
        growth plate and impaired chondrocyte hypertrophy
      explanation: Links the differentiation block to the growth deficit in the Prkg2-null mouse.
- name: Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    In chondrocytes, cGKII acts as an inhibitory input onto the FGF-MAPK
    cascade by phosphorylating c-Raf-1 at Ser43. Losing that input dysregulates
    FGF2-driven ERK1/2 signalling in a pathway whose excess activity is a
    well-established cause of impaired chondrocyte proliferation in the FGFR3
    chondrodysplasias. This node is deliberately named for the lesion rather
    than for a direction of change. Two of the three source abstracts phrase the
    mutant effect ambiguously - the clause reads equally as the mutant reducing
    ERK activation or as the mutant failing to reduce it - and only
    PMID:37789084 states it unambiguously, that the mutant was unable to
    down-regulate FGF2-induced MAPK signalling. Loss of restraint is therefore
    what the evidence supports; a quantified increase in chondrocyte ERK output
    is not.
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: ABNORMAL
  - preferred_term: Negative regulation of ERK1 and ERK2 cascade
    term:
      id: GO:0070373
      label: negative regulation of ERK1 and ERK2 cascade
    modifier: DECREASED
  - preferred_term: Fibroblast growth factor receptor signaling pathway
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
    modifier: ABNORMAL
  - preferred_term: Peptidyl-serine phosphorylation of c-Raf-1
    term:
      id: GO:0018105
      label: peptidyl-serine phosphorylation
    modifier: DECREASED
  cell_types:
  - preferred_term: Growth-plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Wild-type cGKII downregulated MAPK signalling by reducing ERK1/2
      activation through the upstream phosphorylation of Raf-1 at Ser-43 in a
      cGMP-dependent manner.
    explanation: Defines the normal inhibitory action of cGKII on the FGF-MAPK cascade that the disorder removes.
  - reference: PMID:15869918
    reference_title: Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CNP and 8-bromo-cGMP strongly and dose-dependently inhibited the induction
      of ERK phosphorylation by FGF2 and FGF18 without changing the level of
      FGFR-3
    explanation: >-
      Shows the CNP-cGMP arm restraining FGF-driven ERK activation in
      chondrocytes, the brake that PRKG2 loss removes.
  - reference: PMID:15869918
    reference_title: Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      constitutes the negative cross talk between FGFs and the activity of MAPK
    explanation: >-
      Frames the relationship as reciprocal cross-talk, which is why this node
      is annotated as loss of a negative regulator rather than as a primary
      increase in FGF signalling.
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      functional studies of the novel missense variant, p.Val470Gly, revealed
      that it was unable to down-regulate FGF2-induced MAPK signaling and, thus,
      would be predicted to cause growth delay
    explanation: An independent allele reproduces the same failure of MAPK downregulation, linking it to growth failure.
  downstream:
  - target: Dysregulated SOX9-Dependent Chondrocyte Collagen Program
    causal_link_type: DIRECT
    hypothesis_groups:
    - raf1_mapk_brake_model
    description: >-
      The altered MAPK output feeds directly into the SOX9-controlled collagen
      transcriptional program of the growth-plate chondrocyte.
    evidence:
    - reference: PMID:33106379
      reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.
      explanation: The same mutant proteins alter SOX9-dependent COL10A1 and COL2A1 expression.
- name: Dysregulated SOX9-Dependent Chondrocyte Collagen Program
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    COL10A1 marks hypertrophic chondrocytes and COL2A1 marks the proliferative
    and resting zones. Downregulation of COL10A1 with upregulation of COL2A1
    indicates chondrocytes that fail to advance through hypertrophic
    maturation and remain in an earlier differentiation state.
  cell_types:
  - preferred_term: Growth-plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: Chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  - preferred_term: Chondrocyte hypertrophy
    term:
      id: GO:0003415
      label: chondrocyte hypertrophy
    modifier: DECREASED
  - preferred_term: Collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: ABNORMAL
  - preferred_term: Regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.
    explanation: Directly documents the shifted collagen expression program in the mutant setting.
  - reference: PMID:12193576
    reference_title: Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CNP cannot increase the longitudinal bone growth, and chondrocytic
      proliferation and hypertrophy, and cartilage matrix synthesis in
      Prkg2(-/-) mice
    explanation: >-
      Cartilage matrix synthesis is measured alongside proliferation and
      hypertrophy as a cGKII-dependent output, which is the basis for annotating
      matrix and collagen processes on this node.
  - reference: PMID:19887637
    reference_title: A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These experiments indicate that the R678X mutation is functional,
      resulting in a loss of PRKG2 regulation of COL2 and COL10 mRNA expression.
    explanation: >-
      A naturally occurring bovine PRKG2 nonsense allele independently shows loss
      of collagen-gene regulation. Evidence source is MODEL_ORGANISM because the
      measurement is in cattle.
  downstream:
  - target: Impaired Endochondral Longitudinal Bone Growth
    causal_link_type: DIRECT
    description: >-
      Chondrocytes that do not complete the proliferation-to-hypertrophy
      sequence directly reduce the rate of longitudinal growth generated at the
      physis.
    evidence:
    - reference: PMID:33106379
      reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        have been shown to play a pivotal role in chondrogenic differentiation
        and endochondral bone growth
      explanation: Ties the CNP/NPR-B/cGKII axis, and therefore its failure, to endochondral bone growth.
- name: Impaired Endochondral Longitudinal Bone Growth
  role: consequence
  biological_scale: TISSUE
  description: >-
    Reduced longitudinal growth at the physis produces the disproportionate
    short stature, with the growth deficit falling most heavily on the middle
    and distal limb segments and accompanied by metaphyseal and vertebral
    change.
  biological_processes:
  - preferred_term: Endochondral bone growth
    term:
      id: GO:0003416
      label: endochondral bone growth
    modifier: DECREASED
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  - preferred_term: Growth plate cartilage development
    term:
      id: GO:0003417
      label: growth plate cartilage development
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Growth-plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Growth-plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing was performed in two girls with severe short stature due
      to acromesomelic limb shortening, brachydactyly, mild to moderate
      platyspondyly and progressively increasing metaphyseal alterations of the
      long bones.
    explanation: Documents the skeletal output of the growth deficit in the founding patients.
  - reference: PMID:12193576
    reference_title: Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism
      as a result of impaired endochondral ossification
    explanation: >-
      The mouse null attributes the growth deficit specifically to impaired
      endochondral ossification.
mechanistic_hypotheses:
- hypothesis_group_id: raf1_mapk_brake_model
  hypothesis_label: c-Raf-1 Ser43 MAPK-Brake Model
  status: CANONICAL
  description: >-
    cGKII restrains the FGF-driven MAPK cascade in growth-plate chondrocytes by
    phosphorylating c-Raf-1 at Ser43, and pathogenic alleles lose that
    phosphorylation and with it the regulation it provides. The model is about
    the missing brake; it does not by itself specify how far ERK1/2 output moves
    in a growth plate. This is the canonical model for AMDP because it
    is the readout against which every human PRKG2 allele has been assayed:
    the founding nonsense and frameshift alleles, the p.Asp761Glufs*34 allele
    from an independent family, and the first missense allele p.Val470Gly all
    fail the same Raf-1/ERK test. It also connects AMDP to the wider growth-plate
    literature, where excess FGFR3-MAPK signalling is the established cause of
    achondroplasia and where CNP-cGMP is the physiological counterweight.
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      alter the downstream mitogen activation protein kinase signalling pathway
      by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce
      ERK1/2 activation in response to fibroblast growth factor 2
    explanation: The founding human study establishes the Raf-1/ERK readout for AMDP alleles.
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      functional studies of the novel missense variant, p.Val470Gly, revealed
      that it was unable to down-regulate FGF2-induced MAPK signaling and, thus,
      would be predicted to cause growth delay
    explanation: >-
      An independent allele class reproduces the same failure, which is what
      makes this the canonical model. This is also the one source that states
      the direction unambiguously - the mutant is unable to down-regulate MAPK
      signalling - where the other two abstracts phrase it in a way that reads
      both ways.
- hypothesis_group_id: sox9_nuclear_exclusion_switch
  hypothesis_label: SOX9 Nuclear-Exclusion Switch Model
  status: ALTERNATIVE
  description: >-
    cGKII acts as the switch that ends proliferation and starts hypertrophic
    differentiation by excluding SOX9 from the chondrocyte nucleus; without it,
    SOX9 persists and cells accumulate in a postmitotic but non-hypertrophic
    state. The model rests on the cGKII-deficient KMI rat, where SOX9 knockdown
    rescues the differentiation block, and it is attractive for AMDP because it
    predicts exactly the collagen shift measured in the human alleles: SOX9
    drives COL2A1 and represses COL10A1, and the human mutants upregulate COL2A1
    while downregulating COL10A1. It is curated as ALTERNATIVE rather than
    canonical because no human AMDP allele has been tested for SOX9
    localisation.
  evidence:
  - reference: PMID:15466490
    reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a novel role of cGKII as a molecular switch, coupling the cessation of
      proliferation and the start of hypertrophic differentiation of
      chondrocytes through attenuation of Sox9 function
    explanation: States the model in full, in the naturally occurring rat cGKII mutant.
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.
    explanation: >-
      The human alleles produce a SOX9-dependent collagen shift in the direction
      this model predicts, which is suggestive but does not localise SOX9.
- hypothesis_group_id: gsk3b_beta_catenin_route
  hypothesis_label: GSK-3beta / beta-Catenin Hypertrophy Route
  status: ALTERNATIVE
  description: >-
    cGKII phosphorylates and inactivates GSK-3beta, sparing beta-catenin and
    permitting the canonical Wnt output that drives chondrocyte hypertrophy.
    This is the only one of the three models tested by genetic epistasis in a
    mammal: removing one Gsk3b allele partially rescues the Prkg2-null growth
    plate. The rescue is partial, which is itself the argument that GSK-3beta is
    one route rather than the whole mechanism, and no human AMDP data address
    it.
  evidence:
  - reference: PMID:18551195
    reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data indicate that hypertrophic differentiation of growth plate
      chondrocytes during skeletal growth is promoted by phosphorylation and
      inactivation of GSK-3beta by cGKII.
    explanation: States the model's central claim.
  - reference: PMID:18551195
    reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      were partially rescued by haploinsufficiency of Gsk3b
    explanation: >-
      The rescue is explicitly partial, which is why this is curated as one
      contributing route rather than as the canonical mechanism.
  notes: >-
    The three groups are not mutually exclusive. A single kinase with several
    substrates can act through all of them at once, and the growth-plate
    phenotypes they predict overlap. What separates them for curation purposes
    is which has been tested in human AMDP alleles, which is only the first.
phenotypes:
- category: Skeletal
  name: Severe Disproportionate Short Stature
  description: >-
    Short stature is severe and disproportionate, and worsens with age on
    longitudinal follow-up.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37789084
    reference_title: "Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is an extremely rare autosomal recessive skeletal dysplasia characterized
      by severe disproportionate short stature presenting with acromesomelia
    explanation: States severe disproportionate short stature as a defining feature.
- category: Skeletal
  name: Acromesomelic Limb Shortening
  description: >-
    Limb shortening predominantly affects the middle and distal segments. It is
    not invariable: one reported family had no acromesomelic shortening.
  phenotype_term:
    preferred_term: Acromesomelia
    term:
      id: HP:0003086
      label: Acromesomelia
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two girls with severe short stature due to acromesomelic limb shortening
    explanation: The founding patients show the acromesomelic pattern.
- category: Skeletal
  name: Brachydactyly
  description: >-
    Generalised brachydactyly with cone-shaped epiphyses of the middle and
    proximal phalanges.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:36504352
    reference_title: Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      moderate brachydactyly with cone-shaped epiphyses of the middle and
      proximal phalanges
    explanation: The sibling series documents brachydactyly with cone-shaped epiphyses.
- category: Skeletal
  name: Platyspondyly with Anterior Vertebral Beaking
  description: >-
    Mild to moderate platyspondyly with small anterior projections or beaking of
    the vertebral bodies. The finding can become less conspicuous with age.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:36504352
    reference_title: Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination showed platyspondyly with anterior beaking of the
      vertebral bodies, stubby long bones with metaphyseal flaring
    explanation: Documents platyspondyly with anterior vertebral beaking in molecularly confirmed siblings.
- category: Skeletal
  name: Progressive Metaphyseal Alteration of the Long Bones
  description: >-
    Metaphyseal widening, irregularity, and striations, most evident in the
    radius and ulna, which increase over time.
  phenotype_term:
    preferred_term: Metaphyseal widening
    term:
      id: HP:0003016
      label: Metaphyseal widening
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild to moderate platyspondyly and progressively increasing metaphyseal
      alterations of the long bones
    explanation: Establishes progressive metaphyseal change as part of the core phenotype.
- category: Skeletal
  name: Cone-Shaped Epiphyses
  description: >-
    Cone-shaped epiphyses of the middle and proximal phalanges. In the
    spondylometaphyseal-presenting family the coning was subtle and not
    accompanied by shortening.
  phenotype_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  evidence:
  - reference: PMID:36504352
    reference_title: Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      moderate brachydactyly with cone-shaped epiphyses of the middle and
      proximal phalanges
    explanation: Documents cone-shaped phalangeal epiphyses.
- category: Musculoskeletal
  name: Limited Elbow Extension
  description: >-
    Elbow limitation with cubitus varus was described in a molecularly confirmed
    sibling pair.
  phenotype_term:
    preferred_term: Limited elbow extension
    term:
      id: HP:0001377
      label: Limited elbow extension
  evidence:
  - reference: PMID:36504352
    reference_title: Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected biallelic novel variant (c.1635-1G > C) in PRKG2 in two
      brothers with mild to severe short stature, short limbs, cubitus varus,
      and brachydactyly.
    explanation: Reports cubitus varus and, with the elbow limitation noted in the same series, restricted elbow movement.
animal_models:
- name: Prkg2-null mouse
  species: Mouse
  genotype: Prkg2 knockout (homozygous null)
  publication: PMID:12193576
  genes:
  - preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  description: >-
    The engineered cGKII-null mouse is the reference genetic model. It is
    dwarfed with an elongated growth plate and impaired chondrocyte hypertrophy,
    and it is the model in which cGKII was placed downstream of CNP by showing
    that growth-plate CNP overexpression fails to rescue it.
  modeled_mechanisms:
  - target: Loss of cGKII Kinase Activity Downstream of CNP/NPR-B
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      A complete genetic null of the same gene, giving the cleanest available
      readout of what losing cGKII does to the growth plate.
    limitations: >-
      Human AMDP alleles are mostly truncating but not always complete nulls,
      and mouse growth-plate proportions do not reproduce the human
      acromesomelic distribution of shortening.
    readouts:
    - name: Rescue of skeletal defect by growth-plate CNP overexpression
      target: Loss of cGKII Kinase Activity Downstream of CNP/NPR-B
      direction: UNCHANGED
      interpretation: >-
        Supplying the upstream ligand does not correct the phenotype, placing the
        lesion downstream of CNP and cGMP production. This is the negative result
        that makes the epistasis argument.
      evidence:
      - reference: PMID:12193576
        reference_title: Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          targeted expression of CNP in the growth plate chondrocytes fails to
          rescue the skeletal defect of Prkg2(-/-) mice
        explanation: Reports the rescue failure directly.
    evidence:
    - reference: PMID:12193576
      reference_title: Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This study provides in vivo and in vitro genetic evidence that cGKII
        plays a critical role in CNP-mediated endochondral ossification.
      explanation: Supports treating the mouse null as informative for the cGKII node.
  - target: Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The same null is the system in which the GSK-3beta route was identified
      and tested by compound genetics.
    limitations: >-
      The Gsk3b haploinsufficiency rescue is partial, so the model demonstrates
      that this route contributes without establishing how much of the phenotype
      it carries; nothing equivalent has been measured in human AMDP.
    readouts:
    - name: Growth plate length and chondrocyte hypertrophy under Gsk3b haploinsufficiency
      target: Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling
      direction: RESTORED
      interpretation: >-
        Partial correction of the elongated growth plate when one Gsk3b allele is
        removed, the genetic test that puts GSK-3beta on the causal path.
      evidence:
      - reference: PMID:18551195
        reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the growth retardation and elongated growth plate associated with
          cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b
        explanation: Reports the compound-mutant rescue and its partiality.
    evidence:
    - reference: PMID:18551195
      reference_title: Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        in mice, cGKII deficiency results in dwarfism
      explanation: Establishes the mouse null as a growth-phenotype model of cGKII loss.
- name: Komeda miniature rat Ishikawa (KMI)
  species: Rat
  genotype: Prkg2 (mri) deletion, homozygous
  publication: PMID:15466490
  genes:
  - preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  description: >-
    A naturally occurring recessive cGKII deletion in the rat, with longitudinal
    growth retardation and an expanded growth plate packed with postmitotic but
    non-hypertrophic chondrocytes. It is the system in which the SOX9
    nuclear-exclusion model was established.
  modeled_mechanisms:
  - target: Persistent Nuclear SOX9 in Postmitotic Chondrocytes
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The KMI growth plate shows the retained nuclear SOX9 and the
      differentiation arrest that define this node, and SOX9 knockdown rescues
      the arrest ex vivo.
    limitations: >-
      The SOX9 localisation result comes entirely from rat tissue and cultured
      rat chondrocytes; no human AMDP allele has been tested for it, which is
      why the node it supports is curated under an ALTERNATIVE hypothesis group.
    readouts:
    - name: Nuclear SOX9 in postmitotic growth-plate chondrocytes
      target: Persistent Nuclear SOX9 in Postmitotic Chondrocytes
      direction: INCREASED
      interpretation: >-
        SOX9 that should have been cleared from the nucleus at the end of
        proliferation is still present, marking the differentiation arrest.
      evidence:
      - reference: PMID:15466490
        reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The expression of Sox9, an inhibitory regulator of hypertrophic
          differentiation, persisted in the nuclei of postmitotic chondrocytes
          of the KMI growth plate.
        explanation: Reports the localisation measurement in affected animals.
    evidence:
    - reference: PMID:15466490
      reference_title: Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        KMIs showed an expanded growth plate and impaired bone healing with
        abnormal accumulation of postmitotic but nonhypertrophic chondrocytes.
      explanation: Establishes the growth-plate phenotype that makes the rat informative for this node.
- name: Angus cattle PRKG2 R678X dwarfism
  species: Cattle
  genotype: PRKG2 p.Arg678* (R678X) homozygous
  publication: PMID:19887637
  genes:
  - preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  description: >-
    A naturally occurring nonsense PRKG2 allele segregating in American Angus
    cattle causes disproportionate dwarfism and was the first evidence that
    PRKG2 loss impairs longitudinal growth in a large mammal.
  modeled_mechanisms:
  - target: Dysregulated SOX9-Dependent Chondrocyte Collagen Program
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The bovine truncating allele reproduces the loss of PRKG2 control over
      COL2 and COL10 expression seen with the human alleles.
    limitations: >-
      Bovine growth-plate biology and body proportions differ from human, and
      the cattle phenotype is described as dwarfism without the acromesomelic
      radiographic detail used to define the human entity. The direction of the
      collagen change also diverges: dwarf cattle show COL10 mRNA increased,
      whereas the human alleles downregulate COL10A1. What the two systems agree
      on is that PRKG2 loss removes regulation of the collagen genes, not which
      way each transcript moves, so the model supports the regulatory claim at
      this node and not the human direction of effect.
    readouts:
    - name: COL2 and COL10 mRNA expression
      target: Dysregulated SOX9-Dependent Chondrocyte Collagen Program
      direction: INCREASED
      interpretation: >-
        Loss of PRKG2 regulation raises collagen transcript levels in dwarf
        cattle, the same regulatory node dysregulated by the human alleles.
      evidence:
      - reference: PMID:19887637
        reference_title: A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          COL2 and COL10 mRNA expression was increased in dwarf cattle compared
          with unaffected cattle.
        explanation: Reports the direct transcript measurement in affected animals.
    evidence:
    - reference: PMID:19887637
      reference_title: A nonsense mutation in cGMP-dependent type II protein kinase (PRKG2) causes dwarfism in American Angus cattle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These experiments indicate that the R678X mutation is functional,
        resulting in a loss of PRKG2 regulation of COL2 and COL10 mRNA
        expression.
      explanation: Supports treating the bovine allele as informative for the collagen-program node.
- name: Dogo Argentino PRKG2 splice-site dwarfism
  species: Dog
  genotype: PRKG2 c.1634+1G>T homozygous
  publication: PMID:34680883
  genes:
  - preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  description: >-
    Two Dogo Argentino dogs with disproportionate dwarfism were homozygous for a
    PRKG2 splice-donor variant that segregated with the phenotype in a
    nine-animal family, a canine counterpart of the human splice-site alleles.
  modeled_mechanisms:
  - target: Impaired Endochondral Longitudinal Bone Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      A canine PRKG2 loss-of-function allele produces disproportionate dwarfism,
      supporting reduced longitudinal bone growth as the organism-level output of
      PRKG2 loss.
    limitations: >-
      The dogs were characterised clinically and genomically rather than
      histologically, so the growth-plate lesion itself was not measured, and
      canine breed conformation confounds proportionality assessment.
    evidence:
    - reference: PMID:34680883
      reference_title: PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The genotypes of the PRKG2 variant were perfectly associated with the
        phenotype in the studied family of dogs.
      explanation: Segregation in a nine-animal family supports the allele as causal for the growth phenotype.
diagnosis:
- name: Molecular Confirmation of Biallelic PRKG2 Variants
  description: >-
    Diagnosis rests on identifying biallelic PRKG2 variants by exome or genome
    sequencing. Because the radiographic presentation overlaps AMDM and can
    resemble spondylometaphyseal dysplasia, PRKG2 is best reached through a
    broad skeletal-dysplasia panel or untargeted sequencing rather than a
    single-gene test.
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In family 1, WGS and subsequent Sanger sequencing uncovered a homozygous
      pathogenic PRKG2 variant, NM_006259.3:c.2282dup (p.Asp761Glufs*34; online
      supplemental figure 1) in three brothers referred with spondylometaphyseal
      dysplasia
    explanation: >-
      Shows the diagnosis being made by genome sequencing in siblings whose
      referral diagnosis was a different radiographic category.
treatments: []
differential_diagnoses:
- name: Acromesomelic Dysplasia, Maroteaux Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Maroteaux type
    term:
      id: MONDO:0011275
      label: acromesomelic dysplasia 1, Maroteaux type
  description: >-
    The closest differential and the immediate upstream disorder in the same
    signalling axis: biallelic NPR2 variants disable the receptor that generates
    the cGMP signal cGKII transduces.
  distinguishing_features:
  - Biallelic NPR2 variants rather than biallelic PRKG2 variants establish AMDM.
  - >-
    Pronounced generalised cone-shaped epiphyses with phalangeal shortening are
    characteristic of AMDM; in the PRKG2 family presenting as spondylometaphyseal
    dysplasia, coning was subtle and unaccompanied by shortening.
  evidence:
  - reference: PMID:33106379
    reference_title: Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic
      dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic
      peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding
      CNP, cause milder phenotypes.
    explanation: Identifies the upstream NPR2 disorder that AMDP most closely resembles.
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The metaphyses of the distal phalanges were somewhat cone-shaped in one
      child, but not pronounced, generalised or associated with shortening, as
      seen in AMDM.
    explanation: Gives the radiographic contrast between this PRKG2 family and AMDM.
- name: Spondylometaphyseal Dysplasia
  description: >-
    One PRKG2 family was referred with spondylometaphyseal dysplasia and had no
    acromesomelic shortening, so PRKG2 belongs in the differential of that
    radiographic category as well as of acromesomelic dysplasia.
  distinguishing_features:
  - >-
    Long slender femoral necks with platyspondyly and anterior vertebral body
    projections, without acromesomelic shortening, was the presenting pattern in
    the PRKG2 family reported by the 100,000 Genomes Project.
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, family 1 exhibited a skeletal phenotype characterised by
      spondylometaphyseal dysplasia, rather than acromesomelic dysplasia as
      expected in AMDP and AMDM.
    explanation: Documents the spondylometaphyseal presentation of biallelic PRKG2 loss.
discussions:
- discussion_id: cnp_axis_pharmacology_in_amdp
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  - pathophysiology#Loss of cGKII Kinase Activity Downstream of CNP/NPR-B
  prompt: >-
    Would vosoritide, which acts upstream of cGKII, be expected to fail in AMDP
    where it succeeds in NPR2 deficiency?
  rationale: >-
    Vosoritide raises CNP signalling through NPR-B, which sits upstream of
    cGKII. A 2026 phase 2 basket trial reported a marked growth-velocity gain in
    children with heterozygous NPR2 variants, so the axis is pharmacologically
    tractable where receptor signalling is merely reduced. AMDP is the harder
    case in principle: the receptor is intact and it is the intracellular
    effector that is absent, so there may be nothing left to transduce the
    agonised signal. The mouse epistasis result points the same way, since
    growth-plate CNP overexpression fails to rescue the Prkg2-null skeleton.
    Against that, the human AMDP alleles are not all complete nulls and residual
    cGKII might be drivable. No treatment data of any kind have been published
    for AMDP, so this entry carries no treatments section rather than an
    inferred one. The `treatments: []` section is deliberately empty and present
    rather than absent, so that the absence of published management is a curated
    statement rather than an omission.
  evidence:
  - reference: PMID:41967490
    reference_title: A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vosoritide led to marked increases in growth velocity in children with
      RASopathies, ACAN, and NPR2 deficiency
    explanation: >-
      Establishes that CNP-analogue therapy works in a related axis disorder.
      Support is partial because the trial enrolled heterozygous NPR2 carriers,
      not AMDP or biallelic NPR2 disease.
  - reference: PMID:12193576
    reference_title: Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      targeted expression of CNP in the growth plate chondrocytes fails to
      rescue the skeletal defect of Prkg2(-/-) mice
    explanation: >-
      The mouse null is the closest available test of upstream agonism against
      cGKII loss, and it fails; support is partial because a complete mouse null
      may be a harsher test than a human hypomorphic genotype.
- discussion_id: prkg2_downstream_route_arbitration
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#raf1_mapk_brake_model
  - mechanistic_hypotheses#sox9_nuclear_exclusion_switch
  - mechanistic_hypotheses#gsk3b_beta_catenin_route
  prompt: >-
    Which cGKII substrate route carries the human AMDP phenotype, and in what
    proportion?
  rationale: >-
    Three routes have been proposed from the same kinase - c-Raf-1 Ser43 with
    MAPK restraint, SOX9 nuclear exclusion, and GSK-3beta inactivation with
    beta-catenin accumulation - each established in a different system, and none
    excludes the others. Only the first has been assayed against human AMDP
    alleles, and it was chosen as the assay largely because it was already the
    published readout rather than because it was shown to dominate. A single
    patient-derived chondrocyte or iPSC model measuring all three readouts on the
    same alleles would arbitrate this; the iPSC line already exists for one AMDP
    proband, so the experiment is tractable.
  proposed_experiments:
  - experiment_id: amdp_three_readout_arbitration
    name: Parallel three-readout assay of AMDP alleles in a chondrogenic model
    description: >-
      Express the reported AMDP alleles, spanning truncating, splice and missense
      classes, in a chondrogenic system and measure FGF2-induced ERK1/2
      phosphorylation, SOX9 nuclear localisation, and GSK-3beta phosphorylation
      with beta-catenin levels on the same samples, so the three proposed routes
      are compared rather than assumed.
    would_support:
    - pathophysiology#Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade
    - pathophysiology#Persistent Nuclear SOX9 in Postmitotic Chondrocytes
    - pathophysiology#Loss of GSK-3beta Inhibition and Reduced beta-Catenin Signaling
    supporting_outcome:
    - >-
      One readout is disturbed across all allele classes while the others track
      it only weakly, identifying the dominant route.
    - >-
      All three readouts move together across allele classes, supporting a
      genuinely multi-substrate mechanism rather than a single dominant route.
    refuting_outcome:
    - >-
      Allele severity in patients fails to correlate with any of the three
      readouts, indicating that the operative cGKII substrate in the human
      growth plate has not yet been identified.
- discussion_id: prkg2_residual_activity_and_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does residual cGKII activity set AMDP severity, as residual signalling does
    across the GDF5-BMPR1B acromesomelic dysplasias?
  rationale: >-
    A 2025 report attributes an attenuated phenotype to partial rather than
    complete loss of protein function, which is the same dose-response logic
    that separates du Pan syndrome from Grebe dysplasia in the other half of
    ISDS group 16. It is stated there as a hypothesis on one proband, and the
    reported PRKG2 families range from spondylometaphyseal dysplasia with no
    acromesomelic shortening to severe acromesomelic disease without a measured
    activity series to explain the spread. A systematic comparison of residual
    kinase activity against phenotype has not been done.
  attaches_to:
  - pathophysiology#Loss of cGKII Kinase Activity Downstream of CNP/NPR-B
  - genetic#Biallelic PRKG2 Loss-of-Function Variants
  evidence:
  - reference: PMID:41574272
    reference_title: "Case Report: Dual pathogenic mechanism of a PRKG2 missense variant underlies an attenuated phenotype of acromesomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesize that these alterations cause a partial, rather than a
      complete, loss of protein function, which may account for the patient's
      attenuated clinical phenotype.
    explanation: >-
      The dose-response account is offered as a hypothesis about a single
      proband, which is what makes this an open question rather than a curated
      mechanism.
- discussion_id: mapk_defect_direction_in_growth_plate
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of cGKII Restraint on the c-Raf-1/ERK1/2 Cascade
  prompt: >-
    By how much, and in which direction, does chondrocyte ERK1/2 output actually
    move when cGKII is lost?
  rationale: >-
    That cGKII restraint on the cascade is lost is established: mutant protein
    does not phosphorylate c-Raf-1 at Ser43, and one allele is reported as
    unable to down-regulate FGF2-induced MAPK signalling. What is not
    established is the magnitude or even the sign of the resulting change in a
    growth plate. The published assays are transfection experiments in HEK293T
    cells, and the abstract wording in two of the three reports is ambiguous
    between the mutant reducing ERK activation and the mutant failing to reduce
    it, which is a real hazard for anyone reading these entries against the
    sources. This entry therefore annotates the cascade ABNORMAL and its
    negative regulation DECREASED, names the node for the lesion, and leaves the
    output direction open. Measuring phospho-ERK in patient-derived or
    Prkg2-null growth-plate chondrocytes would close it.
notes: >-
  Curated as part of a review of ISDS 2023 nosology group 16 (acromesomelic
  dysplasias). No Orphanet structured record was cited: the pinned Orphadata
  snapshot in data/orphadata/MANIFEST.yaml no longer matches upstream, and
  re-pinning it would rewrite every ORPHA cache file in the repository, which is
  out of scope for this entry.

Acromesomelic Dysplasia PRKG2 Type

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