Acromesomelic Dysplasia PRKG2 Type

Mendelian MONDO:0030553 Pathograph 28 Show in embeddings browser Skeletal Dysplasia

Acromesomelic dysplasia, PRKG2 type is a rare autosomal recessive skeletal dysplasia caused by biallelic PRKG2 variants that impair cGMP-dependent protein kinase II (cGKII). Reported presentations range from marked acromesomelic shortening and brachydactyly to a predominantly spondylometaphyseal dysplasia without obvious acromesomelia, and an attenuated presentation with moderate short stature. Vertebral, metaphyseal, digital and femoral-neck abnormalities vary between and within families. Human-variant cell assays demonstrate deficient regulation of FGF2-induced RAF/ERK signaling, while rodent experiments implicate impaired hypertrophic chondrocyte differentiation through distinct SOX9 and GSK3β-related routes. These experimental molecular findings have not been measured directly in patient growth plates.

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1
Inheritance
12
Pathophys.
32
Phenotypes
3
Gaps
28
Pathograph
1
Genes
1
Medical Actions
3
Differentials
12
Models
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Classifications

ISDS Skeletal Nosology
acromesomelic dysplasias
👪

Inheritance

1
Autosomal Recessive HP:0000007
Both homozygous and compound-heterozygous genotypes occur. Families include consanguineous parents and a reported non-consanguineous couple. The compound-heterozygous girl also had consanguineous parents; compound heterozygosity does not imply absence of consanguinity.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"She is the only child of a healthy non-consanguineous couple"
The homozygous splice-site case was born to reportedly non-consanguineous parents.
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"The child of healthy, consanguineous parents (second cousins)"
Consanguinity in the compound-heterozygous family.
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"the proband is compound heterozygous for NM_006259.3:c.1074del (p.Ala359LeufsTer24) and NM_006259.3c.1630G>T (p.Asp544Tyr), inherited from the mother and father, respectively."
Segregation established maternal and paternal inheritance of the two variants.
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Discussions and Knowledge Gaps

3
How do residual kinase function and tissue-specific effects explain severity across PRKG2 alleles?
KNOWLEDGE GAP OPEN residual_function
Attached to
pathophysiology#Reduced cGKII Kinase Function
The attenuated compound-heterozygous case has direct RNA evidence, but the proposed residual function of its missense/in-frame-deletion products was not measured. The D761Efs*34 family has a predominantly spondylometaphyseal phenotype despite marked signaling defects in heterologous cells. These reports do not establish a quantitative genotype–phenotype rule.
Show evidence (1 reference)
PMID:41574272 SUPPORT BACKGROUND Other
"We hypothesize that these alterations cause a partial, rather than complete, loss of protein function"
The source explicitly presents hypomorphism as a hypothesis.
Which interventions improve growth or function in molecularly confirmed PRKG2 disease?
KNOWLEDGE GAP OPEN treatment_response
Attached to
pathophysiology#Reduced cGKII Kinase Function pathophysiology#Impaired Endochondral Bone Growth
The reported growth-hormone exposure has no published outcome in that case report. CNP overexpression fails to rescue the Prkg2-null mouse, but this is not a human vosoritide trial and cannot settle responses of all partially functional alleles. The phase II vosoritide basket study included RASopathies, ACAN variants and heterozygous NPR2 variants, not PRKG2 disease; its efficacy cannot be transferred to this diagnosis.
Show evidence (3 references)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"GH treatment was started at the age of six."
The paper reports treatment initiation in one patient but supplies no dose, subsequent height outcome or adverse-event assessment.
PMID:12193576 SUPPORT PRIMARY RESULT Model Organism
"targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice"
Relevant negative model rescue, with an explicit limit on clinical extrapolation.
PMID:41967490 SUPPORT PRIMARY RESULT Human Clinical
"Carriers of heterozygous pathogenic/likely pathogenic variants in NPR2"
The basket-trial eligibility concerned the upstream receptor in heterozygous cases, not PRKG2.
How do the measured RAF/ERK, SOX9 and GSK3β-related effects combine in patient growth-plate chondrocytes?
KNOWLEDGE GAP OPEN signaling_integration
Attached to
pathophysiology#Persistent SOX9 Nuclear Activity pathophysiology#Reduced GSK3β Ser9 Phosphorylation pathophysiology#Reduced β-Catenin Signaling pathophysiology#Reduced RAF1 Ser43 Phosphorylation pathophysiology#Persistent FGF2-Induced ERK Activation pathophysiology#Impaired Hypertrophic Chondrocyte Differentiation
The human-variant RAF/ERK assays are heterologous expression experiments. Rodent and engineered-cell studies support SOX9 and GSK3β contributions, but do not place GSK3β upstream of SOX9 exclusion or prove β-catenin necessity. Direct SOX9 phosphorylation is dispensable for the localization effect. The ERK assay direction is established; the unresolved issue is mediation and integration in the relevant human tissue.
Show evidence (1 reference)
PMID:18551195 SUPPORT PRIMARY RESULT In Vitro
"Neither addition of the GSK-3β inhibitor LiCl nor overexpression of GSK-3 βS9A altered cGKII-dependent inhibition of Sox9 nuclear entry"
The tested GSK3β manipulations did not mediate SOX9 localization.
⚙

Pathophysiology

12
Biallelic PRKG2 Variants
Biallelic germline PRKG2 variants initiate this disorder. Molecular consequences differ between alleles; the observed RNA, protein-abundance and signaling defects are represented separately.
PRKG2 hgnc:9416 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRKG2 (hgnc:9416). hgnc:9416 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Aberrant PRKG2 Splicing The c.1630G>T allele activates a cryptic donor and changes exon-13 splicing.
PRKG2 Transcript Depletion Premature termination triggers transcript degradation for the founding variants; this is not universal across PRKG2 alleles.
Reduced cGKII Protein Abundance Some expressed human mutant constructs produce substantially less cGKII protein. These assays do not distinguish reduced synthesis from accelerated turnover.
Reduced cGKII Kinase Function Altered proteins fail to support the tested kinase-dependent signaling response; the relative contributions of low abundance and catalytic impairment are not resolved for every allele.
Show evidence (1 reference)
PMID:33106379 SUPPORT PRIMARY RESULT Human Clinical
"Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified."
Genetic initiating lesion in the original human cases.
Aberrant PRKG2 Splicing
The c.1630G>T allele produces two RNA populations: approximately half of variant-bearing transcripts in the carrier father have a six-nucleotide exon-13 deletion, while the rest retain the missense substitution. This is a transcript observation; the proposed p.Asp544_Arg545del and p.Asp544Tyr protein products were not assayed.
RNA splicing GO:0008380 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal RNA splicing (GO:0008380). GO:0008380 is a biological process from the Gene Ontology.
Experimental models
PRKG2 family fibroblast RNA analysis PRIMARY CELL CULTURE Demonstrates use of a cryptic exon-13 donor.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT In Vitro
"Analysis of the proband’s father revealed aberrant transcripts, which were absent in controls and characterized by a 6-nucleotide truncation of exon 13"
Carrier fibroblast RNA establishes the splice consequence of c.1630G>T.
PRKG2 Transcript Depletion
Nonsense-mediated decay was reported for the original nonsense and frameshift alleles. The later p.Ala359Leufs*24 carrier fibroblast sample showed a 92:8 wild-type:mutant RNA ratio, consistent with mutant-transcript depletion; that ratio alone is not a direct kinetic measurement of decay.
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay GO:0000184 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184). GO:0000184 is a biological process from the Gene Ontology.
Experimental models
PRKG2 family fibroblast RNA analysis PRIMARY CELL CULTURE Shows a 92:8 wild-type:mutant ratio for the maternal frameshift allele.
Downstream
Reduced cGKII Protein Abundance Depletion of a coding transcript can reduce the amount of its protein through reduced available template. This contribution is inferred and does not explain all expression defects.
Show evidence (2 references)
PMID:33106379 SUPPORT PRIMARY RESULT In Vitro
"The mutant transcripts are exposed to nonsense-mediated decay"
Nonsense-mediated decay was reported for the two founding variants; this is allele-specific functional evidence.
PMID:41574272 SUPPORT PRIMARY RESULT In Vitro
"revealed a significant allelic imbalance (wt/mut ratio = 92/8)"
Allelic RNA imbalance in the carrier mother.
Reduced cGKII Protein Abundance
Transient HEK293T expression yielded markedly reduced abundance of R569*, D761Efs*34 and V470G proteins relative to wild type. This is neither a direct protein-stability assay nor evidence that all patient tissues lack protein. The V470G paper reports slightly different reduction thresholds in its figure legend and results; no single precise percentage is assigned here.
Experimental models
Human PRKG2 variants in HEK293T cells CELL LINE Human mutant constructs yield reduced protein abundance.
Downstream
Reduced cGKII Kinase Function Reduced available cGKII contributes to reduced signaling capacity, alongside any intrinsic catalytic defect.
Show evidence (2 references)
PMID:34782440 SUPPORT PRIMARY RESULT In Vitro
"For both variants, cGKII was detected at the predicted size"
Immunoblotting detected the R569* and D761Efs*34 proteins; subsequent densitometry showed markedly reduced abundance.
PMID:37789084 SUPPORT PRIMARY RESULT In Vitro
"The mutant cGKII protein levels were severely reduced compared to wild-type cGKII."
Confirms reduced V470G abundance without adopting the inconsistent numeric thresholds.
Reduced cGKII Kinase Function
cGKII is a cGMP-dependent kinase downstream of CNP/NPR-B. Tested human variants fail to provide normal regulation of RAF/ERK signaling, while the rat mutant lacks a cGMP-stimulated kinase response. Loss of cGMP binding itself has not been demonstrated for every allele.
PRKG2 hgnc:9416 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRKG2 (hgnc:9416). hgnc:9416 is a gene from the HUGO Gene Nomenclature Committee.
cGMP-dependent protein kinase activity GO:0004692 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cGMP-dependent protein kinase activity (GO:0004692). GO:0004692 is a molecular function from the Gene Ontology.
Downstream
Persistent SOX9 Nuclear Activity Loss of cGKII permits persistent SOX9 nuclear localization and activity in rat and transfection systems. The molecular intermediary is unresolved; direct SOX9 S181/S64 phosphorylation is dispensable for this effect.
Reduced GSK3β Ser9 Phosphorylation Reduced cGKII removes phosphorylation input to GSK3β Ser9; recombinant-protein assays directly demonstrate that substrate reaction.
Reduced RAF1 Ser43 Phosphorylation In the tested human-variant expression systems, impaired cGKII is associated with failure to induce RAF1 Ser43 phosphorylation. Purified variant-enzyme/substrate kinetics were not measured.
Impaired Hypertrophic Chondrocyte Differentiation Loss and re-expression experiments establish a contribution of cGKII to hypertrophic differentiation. The graph includes two experimentally supported contributing branches, without claiming that they exhaust its actions.
Show evidence (2 references)
PMID:34782440 SUPPORT PRIMARY RESULT In Vitro
"neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared with WT"
Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"The in vitro kinase assay revealed that the wild-type extract showed a significant increase in the kinase activity by the stimulation with the cGMP analog 8-bromo-cGMP; however, the increase was not observed in the KMI extract"
The cGMP-stimulated kinase response was absent in rat brain extracts.
Persistent SOX9 Nuclear Activity
Persistent nuclear SOX9 and continued SOX9-dependent transcription contribute to impaired hypertrophic progression in the KMI rat. Cultured-cell SOX9 silencing rescues ALP and COL10 readouts. Nuclear exclusion is mechanistically separable from direct SOX9 phosphorylation and from the GSK3β branch.
Experimental models
KMI rat growth-plate chondrocyte cultures PRIMARY CELL CULTURE cGMP or CNP excludes SOX9 from the nucleus in wild-type but not KMI cells.
SOX9 localization and transcription assays CELL LINE Engineered localization and transcription assays dissect the SOX9 contribution.
Bovine R678X cGKII in HuH-7 cells CELL LINE Tests a SOX9-dependent transcriptional consequence of the cattle allele.
Animal models
Komeda miniature rat Ishikawa Rat recapitulates SOX9 persists in nuclei of the abnormal intermediate layer.
Downstream
Impaired Hypertrophic Chondrocyte Differentiation Persistent SOX9 activity contributes to the differentiation defect, as supported by RNA-interference rescue in rat growth-plate chondrocytes.
Show evidence (2 references)
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA level was reversed by the retrovirus-mediated introduction of Sox9 RNAi."
Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
PMID:15466490 SUPPORT PRIMARY RESULT Model Organism
"nuclear localization of Sox9 was clearly visible in the abnormal intermediate layer of the KMI growth plate"
In-vivo localization in the rat.
Reduced GSK3β Ser9 Phosphorylation
Prkg2-null mouse growth plates have reduced phospho-Ser9-GSK3β. Recombinant cGKII phosphorylates this inhibitory site directly. Persistence of GSK3β activity is the mechanistic interpretation; the paper did not directly measure degradation kinetics or all downstream substrates.
Experimental models
cGKII–GSK3β biochemical and cell experiments OTHER Purified proteins directly establish the phosphorylation step.
Downstream
Reduced β-Catenin Signaling Loss of inhibitory Ser9 phosphorylation is proposed to leave GSK3β-dependent β-catenin turnover less restrained. Cell-expression and S9A reporter experiments support this route, but turnover kinetics were not measured.
Impaired Hypertrophic Chondrocyte Differentiation The GSK3β route contributes to delayed hypertrophy: S9A attenuates cGKII-induced markers in cells and Gsk3b haploinsufficiency partially rescues Prkg2-null mice. It is not the upstream mediator of SOX9 nuclear exclusion.
Show evidence (2 references)
PMID:18551195 SUPPORT PRIMARY RESULT In Vitro
"Direct phosphorylation of recombinant GSK-3β at Ser9, the crucial site for inactivation of GSK-3β (10), by recombinant cGKII protein was confirmed by in vitro kinase assay"
Direct biochemical evidence for the kinase-substrate step.
PMID:18551195 SUPPORT PRIMARY RESULT Model Organism
"cGKII deficiency caused similar decreases in β-catenin and Ser9- phosphorylated GSK-3β levels with little effect on the total GSK-3β level in the abnormal intermediate layer."
Mouse growth-plate immunostaining shows the disease-direction change.
Reduced β-Catenin Signaling
Reduced β-catenin immunostaining is observed in Prkg2-null growth plates. cGKII constructs increase cytosolic β-catenin in ATDC5 cells and TCF reporter activity in HEK293 cells. These results support a candidate effector branch; β-catenin necessity for hypertrophic differentiation or rescue was not directly tested, and canonical Wnt-ligand activation was not established.
Experimental models
cGKII–GSK3β biochemical and cell experiments OTHER cGKII increases β-catenin abundance and TCF activity in different cell systems.
Show evidence (4 references)
PMID:18551195 SUPPORT PRIMARY RESULT In Vitro
"using TOPflash and FOP- flash reporter plasmids in HEK293 cells transfected with constitutively active cGKII"
TCF reporter assays were in HEK293 cells; cytosolic β-catenin protein measurements were in ATDC5 cells.
PMID:18551195 SUPPORT BACKGROUND Other
"we note that there is no direct evidence of cGKII being involved in the canonical Wnt pathway."
Authors explicitly limit the pathway interpretation.
PMID:18551195 SUPPORT PRIMARY RESULT Model Organism
"cGKII deficiency caused similar decreases in β-catenin and Ser9- phosphorylated GSK-3β levels with little effect on the total GSK-3β level in the abnormal intermediate layer."
Mouse growth-plate immunostaining shows the disease-direction change.
+ 1 more reference
Reduced RAF1 Ser43 Phosphorylation
Human mutant cGKII constructs fail to induce normal RAF1 Ser43 phosphorylation in the cGMP/FGF2 assay. This phosphorylation readout is separated from downstream ERK activation.
Experimental models
Human PRKG2 variants in HEK293T cells CELL LINE Mutants fail to induce RAF1 Ser43 phosphorylation.
Downstream
Persistent FGF2-Induced ERK Activation The authors interpret reduced inhibitory RAF1 phosphorylation as the upstream explanation for failure to restrain the MAPK cascade. The expression experiments do not establish Ser43-specific necessity by a RAF1-site rescue.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT In Vitro
"Neither the V470G mutant nor R569* were able to phosphorylate c-RAF at Ser43"
Variant-transfection assays show loss of the measured phosphorylation response.
Persistent FGF2-Induced ERK Activation
In HEK293T expression assays, R569*, D761Efs*34 and V470G fail to reduce FGF2-induced ERK1/2 activation as wild-type cGKII does. This is an experimentally measured signaling phenotype, not a patient growth-plate measurement. Its connection to the SOX9 branch has not been established by these variant assays.
Experimental models
Human PRKG2 variants in HEK293T cells CELL LINE Mutants fail to restrain FGF2-induced ERK1/2 activation.
Show evidence (2 references)
PMID:34782440 SUPPORT PRIMARY RESULT In Vitro
"neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared with WT"
Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
PMID:37789084 SUPPORT PRIMARY RESULT In Vitro
"the V470G mutant variant, as with the R569* positive control, was unable to down-regulate the MAPK pathway, as seen by the failure to reduce ERK1/2 activation"
The direction is clear in the complete functional results.
Impaired Hypertrophic Chondrocyte Differentiation
Delayed transition from postmitotic to hypertrophic chondrocytes produces an abnormal intermediate growth-plate layer in rodent models. In rat primary cultures, ALP and COL10 are reduced and recover after cGKII expression or SOX9 silencing. Collagen measurements are context dependent: Angus mutant growth plates showed increased COL2 and COL10 RNA, so reduced COL10 is not universal across models.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
chondrocyte differentiation GO:0002062 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chondrocyte differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology.
Experimental models
KMI rat growth-plate chondrocyte cultures PRIMARY CELL CULTURE Primary mutant cells reproduce and permit rescue of the differentiation defect.
cGKII–GSK3β biochemical and cell experiments OTHER Phosphorylation-resistant GSK3β attenuates the cGKII-induced hypertrophic markers.
Animal models
Prkg2-null mouse Mouse recapitulates Reproduces deficient growth-plate hypertrophic progression.
Prkg2-null mouse with Gsk3b haploinsufficiency Mouse perturbs Genetic reduction of GSK3β partially ameliorates the differentiation/growth defect.
Komeda miniature rat Ishikawa Rat recapitulates Rat histology demonstrates the abnormal intermediate layer.
Downstream
Impaired Endochondral Bone Growth Disrupted growth-plate maturation compromises longitudinal endochondral bone growth. This tissue-level bridge is supported by rodent histology and bone-length phenotypes.
Show evidence (3 references)
PMID:15466490 SUPPORT PRIMARY RESULT Model Organism
"the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not started hypertrophic differentiation."
Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA level was reversed by the retrovirus-mediated introduction of Sox9 RNAi."
Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
PMID:19887637 SUPPORT PRIMARY RESULT Model Organism
"Real-time PCR of COL10 indicated an increase in expression in dwarfs compared with normal individuals"
The cattle result limits generalization of the rat marker direction.
Impaired Endochondral Bone Growth
Reduced endochondral growth shortens long bones and vertebrae in rodent models and provides the tissue-level explanation for the human skeletal growth disorder. The distribution and severity of human shortening vary, and model experiments do not explain each individual radiographic shape abnormality.
endochondral ossification GO:0001958 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology.
Animal models
Prkg2-null mouse Mouse recapitulates Prkg2 deficiency impairs skeletal growth, and growth-plate CNP overexpression does not rescue this defect.
Angus cattle with PRKG2 R678X Cattle recapitulates Naturally occurring disruption of the homologous gene produces impaired skeletal growth.
Dogo Argentino PRKG2 splice-site candidate Dog partially recapitulates Comparative genetic evidence links the candidate splice defect to abnormal skeletal growth.
Downstream
Disproportionate short stature Impaired growth-plate growth explains short-limb stature; applying model findings to the human distribution is a biological inference.
Acromesomelic limb shortening Disrupted endochondral growth contributes to middle/distal limb shortening when this presentation is present; some families lack obvious acromesomelia.
Brachydactyly Reduced growth of digital bones can contribute to brachydactyly; neither its frequency nor the exact regional developmental explanation is established by the model experiments.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT Model Organism
"the longitudinal lengths of femora, tibiae, and vertebrae, all of which are formed through endochondral ossification, were 20%-30% shorter in KMI than in wild type"
Longitudinal skeletal growth defect in the rat model.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acromesomelic Dysplasia PRKG2 Type Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

32
Head and Neck 8
Relative macrocephaly HP:0004482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Relative macrocephaly (HP:0004482). HP:0004482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Relative macrocephaly and slow linear growth were noted at 9 months old."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Prominent forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Thick eyebrows HP:0000574 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thick eyebrow (HP:0000574). HP:0000574 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Synophrys HP:0000664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synophrys (HP:0000664). HP:0000664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Anteverted nares HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Broad philtrum HP:0000289 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad philtrum (HP:0000289). HP:0000289 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Long philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"anteverted nose, long philtrum and large halluces"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Integument 2
Prominent fingertip pads HP:0001212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent fingertip pads (HP:0001212). HP:0001212 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"mildly short fingers with fetal pads"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Generalized hypertrichosis HP:0004554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypertrichosis (HP:0004554). HP:0004554 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Generalized hirsutism, widening of wrists, mild limitation in elbow extension, and interphalangeal joint laxity were also noted."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Limbs 14
Acromesomelic limb shortening Acromesomelia HP:0003086 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acromesomelia (HP:0003086). HP:0003086 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33106379 SUPPORT PRIMARY RESULT Human Clinical
"two girls with severe short stature due to acromesomelic limb shortening"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"The clinical findings included a prominent forehead, a broad chest, mild lumbar hyperlordosis, shortened forearms, mild brachydactyly of the hands and feet, relatively large and broad great toes and a sandal gap"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Metaphyseal widening HP:0003016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal widening (HP:0003016). HP:0003016 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36504352 SUPPORT PRIMARY RESULT Human Clinical
"Radiological examination showed platyspondyly with anterior beaking of the vertebral bodies, stubby long bones with metaphyseal flaring"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Limited elbow extension HP:0001377 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limited elbow extension (HP:0001377). HP:0001377 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Generalized hirsutism, widening of wrists, mild limitation in elbow extension, and interphalangeal joint laxity were also noted."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Cubitus varus HP:0025317 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cubitus varus (HP:0025317). HP:0025317 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36504352 SUPPORT PRIMARY RESULT 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."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Radial bowing HP:0002986 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Radial bowing (HP:0002986). HP:0002986 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Skeletal radiographs revealed platyspondyly with anterior beaking of thoracolumbar vertebral bodies, bowing of the radius and ulna, mild metaphyseal irregularities of the long bones, moderate brachydactyly and short and broad phalanges with cone-shaped epiphyses"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Ulnar bowing HP:0003031 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ulnar bowing (HP:0003031). HP:0003031 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Skeletal radiographs revealed platyspondyly with anterior beaking of thoracolumbar vertebral bodies, bowing of the radius and ulna, mild metaphyseal irregularities of the long bones, moderate brachydactyly and short and broad phalanges with cone-shaped epiphyses"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Finger joint hypermobility HP:0006094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Finger joint hypermobility (HP:0006094). HP:0006094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Generalized hirsutism, widening of wrists, mild limitation in elbow extension, and interphalangeal joint laxity were also noted."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Elongated femoral neck HP:0033985 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elongated femoral neck (HP:0033985). HP:0033985 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34782440 SUPPORT PRIMARY RESULT Human Clinical
"development of long, slender femoral necks."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Narrow femoral neck HP:0008819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow femoral neck (HP:0008819). HP:0008819 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34782440 SUPPORT PRIMARY RESULT Human Clinical
"development of long, slender femoral necks."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Short metacarpals HP:0010049 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short metacarpal (HP:0010049). HP:0010049 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"shortening of the metacarpals relative to the phalanges"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Metacarpal pseudoepiphyses Metacarpal pseudoepiphysis HP:0009193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metacarpal pseudoepiphysis (HP:0009193). HP:0009193 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"incomplete pseudo-epiphyses of the first and second metacarpals"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Broad hallux HP:0010055 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad hallux (HP:0010055). HP:0010055 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"The clinical findings included a prominent forehead, a broad chest, mild lumbar hyperlordosis, shortened forearms, mild brachydactyly of the hands and feet, relatively large and broad great toes and a sandal gap"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Sandal gap HP:0001852 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sandal gap (HP:0001852). HP:0001852 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"Feet demonstrating brachydactyly, large and broad great toes and a sandal gap."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Musculoskeletal 7
Platyspondyly HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36504352 SUPPORT PRIMARY RESULT Human Clinical
"platyspondyly with anterior beaking of the vertebral bodies"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Anterior vertebral beaking Beaking of vertebral bodies HP:0004568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Beaking of vertebral bodies (HP:0004568). HP:0004568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36504352 SUPPORT PRIMARY RESULT Human Clinical
"platyspondyly with anterior beaking of the vertebral bodies"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Cone-shaped epiphyses Cone-shaped epiphysis HP:0010579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cone-shaped epiphysis (HP:0010579). HP:0010579 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36504352 SUPPORT PRIMARY RESULT Human Clinical
"moderate brachydactyly with cone-shaped epiphyses of the middle and proximal phalanges"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Lumbar hyperlordosis HP:0002938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lumbar hyperlordosis (HP:0002938). HP:0002938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"The clinical findings included a prominent forehead, a broad chest, mild lumbar hyperlordosis, shortened forearms, mild brachydactyly of the hands and feet, relatively large and broad great toes and a sandal gap"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Thoracolumbar scoliosis HP:0002944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thoracolumbar scoliosis (HP:0002944). HP:0002944 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"A skeletal survey showed mild mesomelia, thoracolumbar scoliosis, and subtle irregular metaphyseal changes."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Delayed skeletal maturation HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"a bone age delay of 1.5 years"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Accelerated skeletal maturation HP:0005616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Accelerated skeletal maturation (HP:0005616). HP:0005616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Her bone age was advanced by 1 year"
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
Growth 1
Disproportionate short stature Disproportionate short-limb short stature HP:0008873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disproportionate short-limb short stature (HP:0008873). HP:0008873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"disproportionate short stature with notably short forearms and hands."
Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
🧬

Genetic Associations

1
Biallelic PRKG2 variants (Causative)
Gene: PRKG2 hgnc:9416 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRKG2 (hgnc:9416). hgnc:9416 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:33106379 SUPPORT PRIMARY RESULT Human Clinical
"Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified."
The founding human genotypes.
PMID:34782440 SUPPORT PRIMARY RESULT Human Clinical
"In family 1, WGS and subsequent Sanger sequencing uncovered a homozygous pathogenic PRKG2 variant, NM_006259.3:c.2282dup (p.Asp761Glufs*34;"
The C-terminal-extension genotype occurred in three brothers.
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Parents were found to be heterozygous for the variant."
Segregation of p.Val470Gly.
+ 2 more references
💊

Medical Actions

1
Reported growth hormone treatment
Category: Therapeutic Action: Growth hormone treatmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Growth hormone treatment, annotated with Hormone Therapy (NCIT:C15445). NCIT:C15445 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Therapy NCIT:C15445
Agent: growth hormone NCIT:C164163 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses growth hormone, annotated with Therapeutic Growth Hormone (NCIT:C164163). NCIT:C164163 is a therapeutic agent from the NCI Thesaurus.
Growth hormone was initiated at age six in the first patient in the 2024 report. This is an individual treatment exposure, not evidence of efficacy or a disorder-specific recommendation; the report provides no treatment response or dose.
Mechanism Target:
Disproportionate short stature — The reported treatment was aimed at growth impairment. No direction or magnitude of treatment response is assigned because the paper reports initiation only.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"GH treatment was started at the age of six."
The paper reports treatment initiation in one patient but supplies no dose, subsequent height outcome or adverse-event assessment.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"GH treatment was started at the age of six."
The paper reports treatment initiation in one patient but supplies no dose, subsequent height outcome or adverse-event assessment.
🔬

Diagnosis

2
Clinical and radiographic assessment with molecular confirmation
Evaluate disproportionate growth and limb, hand, femoral-neck and spinal findings. A predominantly spondylometaphyseal presentation does not exclude PRKG2 disease. Exome or genome analysis can identify biallelic variants; segregation and, where needed, variant-specific RNA or functional studies help interpretation. A negative older panel can reflect omission of PRKG2.
Show evidence (3 references)
PMID:34782440 SUPPORT PRIMARY RESULT Human Clinical
"WGS and subsequent Sanger sequencing uncovered a homozygous pathogenic PRKG2 variant"
Genome sequencing and confirmation in the spondylometaphyseal family.
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"Initial DNA diagnostics using a skeletal dysplasia gene panel (166 genes) failed to identify causative variants."
The text attributes the negative panel to the gene not being included at that time.
PMID:41574272 SUPPORT PRIMARY RESULT In Vitro
"This variant leads to the production of two aberrant transcript populations"
RNA analysis clarifies a coding variant with an additional splice effect.
Assessment of growth and skeletal maturation
Endocrine and growth assessment complements skeletal imaging. Normal IGF-1 and other routine endocrine results occurred in reported cases; normal results do not exclude this primary skeletal disorder. Bone age may be delayed or advanced, so neither direction is a required diagnostic criterion.
Show evidence (2 references)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"Levels of TSH, free T4, IGF-1, parathyroid hormone, ionized calcium, and 25-hydroxyvitamin D were within the normal range."
Normal biochemical screening in one affected child.
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"The hormonal evaluation showed a normal IGF-1"
Normal IGF-1 in another molecularly diagnosed child.
📈

Progression

2
Infancy and childhood
Growth deficiency may become apparent during infancy despite normal birth length, although prenatal long-bone shortening or short birth length has also been reported. In the attenuated case, height was −2.81 SD at one year, −3.0 SD at eight years and −2.81 SD at nine years; this does not establish universal progressive worsening.
Show evidence (3 references)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"The parents first noticed growth retardation at the age of 6 months"
Infantile recognition in the attenuated case.
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"Relative macrocephaly and slow linear growth were noted at 9 months old."
Infantile recognition in the first 2024 patient.
PMID:37789084 SUPPORT PRIMARY RESULT Human Clinical
"birth length 42 cm (−3.5 SDS)"
The second 2024 patient was short at birth.
Variable skeletal evolution
The founding two girls had progressively increasing metaphyseal alterations. Annual observation of one older brother from ages five to twenty showed worsening short stature but less conspicuous platyspondyly and anterior beaking. His younger brother had less severe short stature and greater vertebral involvement at comparable ages. These small case series do not define a uniform natural history.
Show evidence (2 references)
PMID:33106379 SUPPORT PRIMARY RESULT Human Clinical
"mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones"
Founding two-patient observation.
PMID:36504352 SUPPORT PRIMARY RESULT 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."
Longitudinal observation of one brother, not the whole syndrome.
📊

Prevalence

1
Published molecularly characterized families
Cases In Literature
The 2024 report summarized ten individuals from seven families, including its two new patients. This is a dated literature count rather than a population prevalence estimate; the later compound-heterozygous case expands that literature.
Show evidence (1 reference)
PMID:37789084 SUPPORT BACKGROUND Other
"variants have been reported in 10 individuals from seven different families"
The surrounding 2024 discussion counts six variants in ten individuals from seven families. No population denominator was studied.
🔀

Differential Diagnoses

3

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 generalized cone-shaped epiphyses with phalangeal shortening are characteristic of AMDM. In the PRKG2 family presenting as spondylometaphyseal dysplasia, the subtle coning involved distal phalangeal metaphyses and was unaccompanied by shortening; these are anatomically distinct observations.
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.
Hypochondroplasia
Overlapping Features The attenuated compound-heterozygous case was initially suspected to have hypochondroplasia before negative FGFR3 testing and subsequent identification of PRKG2 variants.
Distinguishing Features
  • The PRKG2 presentation may include mild forearm and digital shortening with slender elongated femoral necks. Molecular testing distinguishes the conditions; the report does not define a validated radiographic decision rule.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT Human Clinical
"hypochondroplasia was initially suspected. However, no pathogenic variants in the FGFR3 gene were identified."
Directly documents the diagnostic overlap.
🧫

Experimental Models

7
Human PRKG2 variants in HEK293T cells CELL_LINE
Transient expression compared human WT cGKII with R569*, D761Efs*34 and, in a later study, V470G. Cells were challenged with a cGMP analog and FGF2; immunoblots measured cGKII abundance, RAF1 Ser43 phosphorylation and ERK1/2 activation. The studies used three biological experiments for their signaling comparisons.
Publication
PMID:34782440
Pathograph links
Reduced cGKII Protein Abundance recapitulates fidelity: moderate Human mutant constructs yield reduced protein abundance.
Limitations: Overexpression does not measure endogenous patient protein levels or distinguish synthesis from turnover.
Show evidence (2 references)
PMID:34782440 SUPPORT PRIMARY RESULT In Vitro
"For both variants, cGKII was detected at the predicted size"
Immunoblotting detected the R569* and D761Efs*34 proteins; subsequent densitometry showed markedly reduced abundance.
+ 1 more reference
Reduced RAF1 Ser43 Phosphorylation recapitulates fidelity: moderate Mutants fail to induce RAF1 Ser43 phosphorylation.
Limitations: The assay does not independently establish purified-enzyme kinetics or RAF1-site necessity.
Show evidence (1 reference)
PMID:37789084 SUPPORT PRIMARY RESULT In Vitro
"Neither the V470G mutant nor R569* were able to phosphorylate c-RAF at Ser43"
Variant-transfection assays show loss of the measured phosphorylation response.
Persistent FGF2-Induced ERK Activation recapitulates fidelity: moderate Mutants fail to restrain FGF2-induced ERK1/2 activation.
Limitations: HEK293T cells are not growth-plate chondrocytes; this does not directly connect ERK activation to SOX9 or patient cartilage behavior.
Show evidence (2 references)
PMID:34782440 SUPPORT PRIMARY RESULT In Vitro
"neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared with WT"
Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
+ 1 more reference
PRKG2 family fibroblast RNA analysis PRIMARY_CELL_CULTURE
RT-PCR and targeted cDNA sequencing examined the two compound-heterozygous alleles. The carrier father had two c.1630G>T-bearing RNA populations, and the carrier mother showed marked depletion of c.1074del-bearing RNA. The paper predicts protein consequences and a hypomorphic mechanism but does not measure those proteins or their kinase activity.
Cell source
Dermal fibroblasts from the proband, parents and a healthy control
Publication
PMID:41574272
Pathograph links
Aberrant PRKG2 Splicing recapitulates fidelity: moderate Demonstrates use of a cryptic exon-13 donor.
Limitations: The approximately half-spliced estimate is reported from the carrier father; no patient chondrocyte experiment was performed.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT In Vitro
"Analysis of the proband’s father revealed aberrant transcripts, which were absent in controls and characterized by a 6-nucleotide truncation of exon 13"
Carrier fibroblast RNA establishes the splice consequence of c.1630G>T.
PRKG2 Transcript Depletion recapitulates fidelity: moderate Shows a 92:8 wild-type:mutant ratio for the maternal frameshift allele.
Limitations: Allelic imbalance is consistent with decay but is not a transcript half-life or NMD-inhibitor rescue measurement.
Show evidence (1 reference)
PMID:41574272 SUPPORT PRIMARY RESULT In Vitro
"revealed a significant allelic imbalance (wt/mut ratio = 92/8)"
Measured maternal allelic RNA imbalance.
KMI rat growth-plate chondrocyte cultures PRIMARY_CELL_CULTURE
Cultures reproduce deficient ALP and COL10 induction without a significant difference in proliferation. Adenoviral cGKII expression and SOX9 RNA interference rescue differentiation readouts. CNP fails to rescue the mutant-cell response, whereas BMP2 stimulates differentiation markers.
Cell source
Primary tibial growth-plate chondrocytes from wild-type and KMI rats
Publication
PMID:15466490
Pathograph links
Impaired Hypertrophic Chondrocyte Differentiation recapitulates fidelity: moderate Primary mutant cells reproduce and permit rescue of the differentiation defect.
Limitations: Culture rescue is not a demonstrated in-vivo treatment.
Readouts
ALP and COL10 after SOX9 silencing
Direction: RESTORED
Interpretation: Silencing reverses the selected deficient differentiation readouts.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA level was reversed by the retrovirus-mediated introduction of Sox9 RNAi."
Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
Show evidence (2 references)
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA level was reversed by the retrovirus-mediated introduction of Sox9 RNAi."
Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
+ 1 more reference
Persistent SOX9 Nuclear Activity recapitulates fidelity: moderate cGMP or CNP excludes SOX9 from the nucleus in wild-type but not KMI cells.
Limitations: The intermediary remains unknown.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"Treatment with the cGMP analog 8-bromo-cGMP inhibited nuclear entry of Sox9 in wild-type cells, whereas it did not in KMI cells."
Primary-cell localization result.
SOX9 localization and transcription assays CELL_LINE
cGKII expression alters SOX9 localization and SOX9-dependent collagen readouts. Phosphorylation-deficient SOX9 and forced nuclear-localization constructs distinguish nuclear entry from direct SOX9 phosphorylation. The cell systems and readouts differ and are not pooled as one chondrocyte experiment.
Cell source
HeLa localization assays, HuH-7 COL2 expression assays, and ATDC5 hypertrophic cultures
Publication
PMID:15466490
Pathograph links
Persistent SOX9 Nuclear Activity perturbs fidelity: moderate Engineered localization and transcription assays dissect the SOX9 contribution.
Limitations: HeLa and HuH-7 are heterologous cells; COL2/COL10 readouts are not patient-cartilage measurements.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT In Vitro
"the direct phosphorylation of Sox9 is dispensable for its attenuation by cGKII."
Phosphosite-mutant evidence limits the direct phosphorylation model.
cGKII–GSK3β biochemical and cell experiments OTHER
Recombinant kinase assays establish GSK3β Ser9 phosphorylation. ATDC5 and primary chondrocyte experiments examine hypertrophic markers; ATDC5 measures cytosolic β-catenin, while HEK293 hosts TCF reporters and Axin co-immunoprecipitation. Constitutively active cGKII and phosphorylation-resistant GSK3β S9A probe pathway function. LiCl is a laboratory perturbation, not an established AMDP therapy.
Cell source
Purified recombinant proteins; ATDC5, HEK293, HuH-7 and primary mouse chondrocytes
Publication
PMID:18551195
Pathograph links
Reduced GSK3β Ser9 Phosphorylation perturbs fidelity: moderate Purified proteins directly establish the phosphorylation step.
Limitations: Ser9 biology and functional S9A experiments support inactivation; the assay does not directly measure every downstream GSK3β reaction.
Show evidence (1 reference)
PMID:18551195 SUPPORT PRIMARY RESULT In Vitro
"Direct phosphorylation of recombinant GSK-3β at Ser9, the crucial site for inactivation of GSK-3β (10), by recombinant cGKII protein was confirmed by in vitro kinase assay"
Direct biochemical evidence for the kinase-substrate step.
Reduced β-Catenin Signaling perturbs fidelity: moderate cGKII increases β-catenin abundance and TCF activity in different cell systems.
Limitations: No β-catenin loss-of-function epistasis establishes its necessity for hypertrophy, and Axin co-immunoprecipitation is not purified pairwise binding.
Show evidence (2 references)
PMID:18551195 SUPPORT PRIMARY RESULT In Vitro
"using TOPflash and FOP- flash reporter plasmids in HEK293 cells transfected with constitutively active cGKII"
TCF reporter assays were in HEK293 cells; cytosolic β-catenin protein measurements were in ATDC5 cells.
+ 1 more reference
Impaired Hypertrophic Chondrocyte Differentiation perturbs fidelity: moderate Phosphorylation-resistant GSK3β attenuates the cGKII-induced hypertrophic markers.
Limitations: Gsk3b+/− primary cells increased COL10 but not ALP or MMP13; marker effects are not identical across experiments.
Show evidence (1 reference)
PMID:18551195 SUPPORT PRIMARY RESULT In Vitro
"cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3beta."
Functional interference with the proposed GSK3β contribution.
Bovine R678X cGKII in HuH-7 cells CELL_LINE
Human hepatoma cells expressed bovine wild-type or R678X cGKII together with human SOX9. The mutant failed to suppress COL2 RNA to the level seen with wild-type cGKII.
Publication
PMID:19887637
Pathograph links
Persistent SOX9 Nuclear Activity perturbs fidelity: moderate Tests a SOX9-dependent transcriptional consequence of the cattle allele.
Limitations: Not a bovine primary chondrocyte culture, direct localization assay, or human pathogenic-variant experiment.
Show evidence (1 reference)
PMID:19887637 SUPPORT PRIMARY RESULT In Vitro
"Cells transfected with the R678X btPRKG2 vector had a 38% increase in COL2 mRNA compared with cells transfected with WT btPRKG2"
Direct relative COL2 expression result in heterologous cells.
Patient-derived IGIBi007-A iPSC resource CELL_LINE
The reported iPSC line retained pluripotency and trilineage differentiation capacity without major reprogramming-related genetic alterations. It is a resource for future cartilage and treatment studies; the cited abstract does not report differentiated chondrocyte phenotypes or therapeutic rescue.
Cell source
Reprogrammed patient lymphoblastoid cell line carrying p.Asn164Lysfs*2
Publication
PMID:33887582
Show evidence (1 reference)
PMID:33887582 SUPPORT PRIMARY RESULT In Vitro
"We report generation of induced pluripotent stem cell line from lymphoblastoid cell lines of the patient carrying the reported frameshift mutation (p.Asn164Lysfs*2)."
Resource derivation is reported, not a completed skeletal-mechanism experiment.
🐁

Animal Models

5
Prkg2-null mouse
Global cGKII deficiency causes dwarfism and a disorganized, elongated growth plate. Growth-plate CNP overexpression fails to rescue the skeletal defect. Later detailed mouse work shows a postmitotic, poorly hypertrophic intermediate layer, with growth-plate expansion most evident at two to four weeks and persistent bone shortening after that expansion subsides.
Species
Mouse
Genotype
Prkg2−/−
Publication
PMID:12193576
Pathograph links
Impaired Hypertrophic Chondrocyte Differentiation recapitulates fidelity: moderate Reproduces deficient growth-plate hypertrophic progression.
Limitations: A global null is more severe molecularly than some human alleles; the human regional pattern is not reproduced exactly.
Show evidence (1 reference)
PMID:12193576 SUPPORT PRIMARY RESULT Model Organism
"The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral ossification"
Mouse knockout phenotype.
Impaired Endochondral Bone Growth recapitulates fidelity: moderate Prkg2 deficiency impairs skeletal growth, and growth-plate CNP overexpression does not rescue this defect.
Limitations: This is a global-null mouse experiment, not a human treatment trial; the skeletal-growth readout does not isolate a particular chondrocyte differentiation step.
Readouts
Response to growth-plate CNP overexpression
Direction: UNCHANGED
Interpretation: The upstream ligand did not rescue the skeletal growth defect in this null model.
Show evidence (1 reference)
PMID:12193576 SUPPORT PRIMARY RESULT Model Organism
"targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice"
In-vivo negative rescue experiment.
Show evidence (1 reference)
PMID:12193576 SUPPORT PRIMARY RESULT Model Organism
"The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral ossification"
The mouse model reproduces impaired endochondral skeletal growth.
Prkg2-null mouse with Gsk3b haploinsufficiency
Male compound-mutant mice show partial recovery of skeletal growth and growth-plate differentiation compared with Prkg2-null mice. Recovery is incomplete and refers to the deficit relative to wild type, not the proportion of normal bone length attained.
Species
Mouse
Genotype
Prkg2−/−; Gsk3b+/−
Publication
PMID:18551195
Pathograph links
Impaired Hypertrophic Chondrocyte Differentiation perturbs fidelity: moderate Genetic reduction of GSK3β partially ameliorates the differentiation/growth defect.
Limitations: Global Gsk3b dosage reduction does not isolate a chondrocyte-autonomous effect. Only male mice were studied; no human therapeutic efficacy was tested.
Readouts
Excess growth-plate height
Direction: RESTORED
Interpretation: The report quantified 36% recovery of the excessive growth-plate height, with partial COL10 restoration.
Show evidence (1 reference)
PMID:18551195 SUPPORT PRIMARY RESULT Model Organism
"The percentage recovery by the GSK-3 β insufficiency was 36.0%."
Quantified partial growth-plate rescue.
Show evidence (1 reference)
PMID:18551195 SUPPORT PRIMARY RESULT Model Organism
"Genetic rescue of impaired skeletal growth in Prkg2–/– mice by suppression of GSK-3 β was significant, but incomplete"
The compound-genetic experiment establishes contribution of the GSK3β route.
Komeda miniature rat Ishikawa
The naturally occurring approximately 5-kb deletion creates a frameshift and predicted kinase-domain truncation. Rats grow normally initially, then develop shortened limbs and trunk from about four weeks. Growth plates accumulate postmitotic nonhypertrophic cells; experimental tibial fracture healing is also delayed.
Species
Rat
Genotype
Homozygous mri deletion spanning Prkg2 exons 4–5
Publication
PMID:15466490
Pathograph links
Impaired Hypertrophic Chondrocyte Differentiation recapitulates fidelity: moderate Rat histology demonstrates the abnormal intermediate layer.
Limitations: The postnatal onset, fracture experiment and molecular readouts are model observations, not established human clinical complications.
Readouts
Postmitotic nonhypertrophic growth-plate cells
Direction: INCREASED
Interpretation: BrdU-negative, ALP/COL10-negative cells accumulate between proliferative and hypertrophic zones.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT Model Organism
"the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not started hypertrophic differentiation."
Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT Model Organism
"the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not started hypertrophic differentiation."
Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
Persistent SOX9 Nuclear Activity recapitulates fidelity: moderate SOX9 persists in nuclei of the abnormal intermediate layer.
Limitations: Localization alone does not establish the intermediary; the causal silencing experiment was performed in isolated cells.
Show evidence (1 reference)
PMID:15466490 SUPPORT PRIMARY RESULT Model Organism
"nuclear localization of Sox9 was clearly visible in the abnormal intermediate layer of the KMI growth plate"
Direct rat immunolocalization.
Angus cattle with PRKG2 R678X
A naturally occurring recessive nonsense variant cosegregated with dwarfism. The experimental breeding cohort comprised four homozygous affected calves and two heterozygous unaffected calves studied around seven months; long bones and stature were reduced. Growth-plate COL2 and COL10 RNA both increased, while total PRKG2 RNA did not differ detectably.
Species
Cattle
Genotype
Homozygous PRKG2 p.Arg678Ter
Publication
PMID:19887637
Pathograph links
Impaired Endochondral Bone Growth recapitulates fidelity: moderate Naturally occurring disruption of the homologous gene produces impaired skeletal growth.
Limitations: Small cohort with heterozygous controls and shared ancestry. Its increased COL10 RNA differs from reduced COL10 in rat-cell experiments; no universal collagen-X direction or human fracture risk follows.
Show evidence (2 references)
PMID:19887637 SUPPORT PRIMARY RESULT Model Organism
"Animals predicted to be dwarfs by the R678X PRKG2 marker had shorter metatarsals"
Direct bone-length phenotype in the breeding cohort.
+ 1 more reference
Dogo Argentino PRKG2 splice-site candidate
Two affected half-siblings in a nine-dog family had disproportionate dwarfism. Detailed radiography and CT of the male showed forelimb deformity, premature distal ulnar physeal closure and impaired endochondral ossification. The splice-donor variant cosegregated with the phenotype and was prioritized against 795 control genomes.
Species
Dog
Genotype
Homozygous PRKG2 c.1634+1G>T
Publication
PMID:34680883
Pathograph links
Impaired Endochondral Bone Growth partially recapitulates fidelity: moderate Comparative genetic evidence links the candidate splice defect to abnormal skeletal growth.
Limitations: No patient-derived RNA, protein or kinase assay established splice loss in the dogs; the variant remains a strongly supported candidate in this report. The detailed imaging was from one affected male.
Show evidence (1 reference)
PMID:34680883 SUPPORT PRIMARY RESULT Model Organism
"The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs."
Family segregation supports the candidate association.
{ }

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
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.
description: >-
  Acromesomelic dysplasia, PRKG2 type is a rare autosomal recessive skeletal dysplasia caused by biallelic
  PRKG2 variants that impair cGMP-dependent protein kinase II (cGKII). Reported presentations range from marked
  acromesomelic shortening and brachydactyly to a predominantly spondylometaphyseal dysplasia without obvious
  acromesomelia, and an attenuated presentation with moderate short stature. Vertebral, metaphyseal, digital
  and femoral-neck abnormalities vary between and within families. Human-variant cell assays demonstrate deficient
  regulation of FGF2-induced RAF/ERK signaling, while rodent experiments implicate impaired hypertrophic chondrocyte
  differentiation through distinct SOX9 and GSK3β-related routes. These experimental molecular findings have
  not been measured directly in patient growth plates.
prevalence:
- population: Published molecularly characterized families
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The 2024 report summarized ten individuals from seven families, including its two new patients. This is
    a dated literature count rather than a population prevalence estimate; the later compound-heterozygous
    case expands that literature.
  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: OTHER
    quote_role: BACKGROUND
    snippet: variants have been reported in 10 individuals from seven different families
    explanation: >-
      The surrounding 2024 discussion counts six variants in ten individuals from seven families. No population
      denominator was studied.
progression:
- phase: Infancy and childhood
  notes: >-
    Growth deficiency may become apparent during infancy despite normal birth length, although prenatal long-bone
    shortening or short birth length has also been reported. In the attenuated case, height was −2.81 SD at
    one year, −3.0 SD at eight years and −2.81 SD at nine years; this does not establish universal progressive
    worsening.
  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
    quote_role: PRIMARY_RESULT
    snippet: The parents first noticed growth retardation at the age of 6 months
    explanation: Infantile recognition in the attenuated case.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Relative macrocephaly and slow linear growth were noted at 9 months old.
    explanation: Infantile recognition in the first 2024 patient.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: birth length 42 cm (−3.5 SDS)
    explanation: The second 2024 patient was short at birth.
- phase: Variable skeletal evolution
  notes: >-
    The founding two girls had progressively increasing metaphyseal alterations. Annual observation of one
    older brother from ages five to twenty showed worsening short stature but less conspicuous platyspondyly
    and anterior beaking. His younger brother had less severe short stature and greater vertebral involvement
    at comparable ages. These small case series do not define a uniform natural history.
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones
    explanation: Founding two-patient observation.
  - 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
    quote_role: PRIMARY_RESULT
    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: Longitudinal observation of one brother, not the whole syndrome.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Both homozygous and compound-heterozygous genotypes occur. Families include consanguineous parents and
    a reported non-consanguineous couple. The compound-heterozygous girl also had consanguineous parents; compound
    heterozygosity does not imply absence of consanguinity.
  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
    quote_role: PRIMARY_RESULT
    snippet: She is the only child of a healthy non-consanguineous couple
    explanation: The homozygous splice-site case was born to reportedly non-consanguineous parents.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The child of healthy, consanguineous parents (second cousins)
    explanation: Consanguinity in the compound-heterozygous family.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      the proband is compound heterozygous for NM_006259.3:c.1074del (p.Ala359LeufsTer24) and NM_006259.3c.1630G>T
      (p.Asp544Tyr), inherited from the mother and father, respectively.
    explanation: Segregation established maternal and paternal inheritance of the two variants.
genetic:
- name: Biallelic PRKG2 variants
  gene_term:
    preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported alleles include p.Asn164Lysfs*2, p.Arg569*, the C-terminal extension p.Asp761Glufs*34, canonical
    splice-site variants, and p.Val470Gly. The extension retains the kinase domain but impairs tested signaling,
    so not all frameshifts remove that domain. The p.Val470Gly protein has reduced abundance and deficient
    RAF/ERK regulation in transfected cells; an ATP-binding defect remains a structural hypothesis. The compound-heterozygous
    p.Ala359Leufs*24/p.Asp544Tyr case adds RNA evidence: c.1630G>T generates both a shortened exon-13 transcript
    and a transcript retaining the missense change. Its protein products and residual kinase activity were
    predicted rather than measured. The homozygous c.1154+1G>A splice-site variant in the Brazilian case was
    classified as likely pathogenic, with predicted splice disruption but no reported RNA assay or parental
    segregation.
  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
    quote_role: PRIMARY_RESULT
    snippet: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified.
    explanation: The founding human genotypes.
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In family 1, WGS and subsequent Sanger sequencing uncovered a homozygous pathogenic PRKG2 variant, NM_006259.3:c.2282dup
      (p.Asp761Glufs*34;
    explanation: The C-terminal-extension genotype occurred in three brothers.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Parents were found to be heterozygous for the variant.
    explanation: Segregation of p.Val470Gly.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Segregation analysis could not be performed in parents and maternal uncle due to lack of DNA samples.
    explanation: Limitation of the c.1154+1G>A family.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: This variant leads to the production of two aberrant transcript populations
    explanation: The newer missense annotation also conceals an experimentally demonstrated splice effect.
pathophysiology:
- name: Biallelic PRKG2 Variants
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Biallelic germline PRKG2 variants initiate this disorder. Molecular consequences differ between alleles;
    the observed RNA, protein-abundance and signaling defects are represented separately.
  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
    quote_role: PRIMARY_RESULT
    snippet: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified.
    explanation: Genetic initiating lesion in the original human cases.
  genes:
  - preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  downstream:
  - target: Aberrant PRKG2 Splicing
    causal_link_type: DIRECT
    description: The c.1630G>T allele activates a cryptic donor and changes exon-13 splicing.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Analysis of the proband’s father revealed aberrant transcripts, which were absent in controls and characterized
        by a 6-nucleotide truncation of exon 13
      explanation: Carrier fibroblast RNA establishes the splice consequence of c.1630G>T.
  - target: PRKG2 Transcript Depletion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Premature termination triggers transcript degradation for the founding variants; this is not universal
      across PRKG2 alleles.
    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
      quote_role: PRIMARY_RESULT
      snippet: The mutant transcripts are exposed to nonsense-mediated decay
      explanation: >-
        Nonsense-mediated decay was reported for the two founding variants; this is allele-specific functional
        evidence.
    intermediate_mechanisms:
    - Nonsense-mediated decay
  - target: Reduced cGKII Protein Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Some expressed human mutant constructs produce substantially less cGKII protein. These assays do not
      distinguish reduced synthesis from accelerated turnover.
    evidence:
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: For both variants, cGKII was detected at the predicted size
      explanation: >-
        Immunoblotting detected the R569* and D761Efs*34 proteins; subsequent densitometry showed markedly
        reduced abundance.
  - target: Reduced cGKII Kinase Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered proteins fail to support the tested kinase-dependent signaling response; the relative contributions
      of low abundance and catalytic impairment are not resolved for every allele.
    evidence:
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared
        with WT
      explanation: Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
- name: Aberrant PRKG2 Splicing
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    The c.1630G>T allele produces two RNA populations: approximately half of variant-bearing transcripts in
    the carrier father have a six-nucleotide exon-13 deletion, while the rest retain the missense substitution.
    This is a transcript observation; the proposed p.Asp544_Arg545del and p.Asp544Tyr protein products were
    not assayed.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Analysis of the proband’s father revealed aberrant transcripts, which were absent in controls and characterized
      by a 6-nucleotide truncation of exon 13
    explanation: Carrier fibroblast RNA establishes the splice consequence of c.1630G>T.
  biological_processes:
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
- name: PRKG2 Transcript Depletion
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Nonsense-mediated decay was reported for the original nonsense and frameshift alleles. The later p.Ala359Leufs*24
    carrier fibroblast sample showed a 92:8 wild-type:mutant RNA ratio, consistent with mutant-transcript depletion;
    that ratio alone is not a direct kinetic measurement of decay.
  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
    quote_role: PRIMARY_RESULT
    snippet: The mutant transcripts are exposed to nonsense-mediated decay
    explanation: >-
      Nonsense-mediated decay was reported for the two founding variants; this is allele-specific functional
      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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: revealed a significant allelic imbalance (wt/mut ratio = 92/8)
    explanation: Allelic RNA imbalance in the carrier mother.
  biological_processes:
  - preferred_term: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  downstream:
  - target: Reduced cGKII Protein Abundance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Depletion of a coding transcript can reduce the amount of its protein through reduced available template.
      This contribution is inferred and does not explain all expression defects.
    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
      quote_role: PRIMARY_RESULT
      snippet: The mutant transcripts are exposed to nonsense-mediated decay
      explanation: >-
        Nonsense-mediated decay was reported for the two founding variants; this is allele-specific functional
        evidence.
    intermediate_mechanisms:
    - Reduced availability of mRNA for translation
- name: Reduced cGKII Protein Abundance
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Transient HEK293T expression yielded markedly reduced abundance of R569*, D761Efs*34 and V470G proteins
    relative to wild type. This is neither a direct protein-stability assay nor evidence that all patient tissues
    lack protein. The V470G paper reports slightly different reduction thresholds in its figure legend and
    results; no single precise percentage is assigned here.
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: For both variants, cGKII was detected at the predicted size
    explanation: >-
      Immunoblotting detected the R569* and D761Efs*34 proteins; subsequent densitometry showed markedly reduced
      abundance.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The mutant cGKII protein levels were severely reduced compared to wild-type cGKII.
    explanation: Confirms reduced V470G abundance without adopting the inconsistent numeric thresholds.
  downstream:
  - target: Reduced cGKII Kinase Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced available cGKII contributes to reduced signaling capacity, alongside any intrinsic catalytic
      defect.
    evidence:
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: For both variants, cGKII was detected at the predicted size
      explanation: >-
        Immunoblotting detected the R569* and D761Efs*34 proteins; subsequent densitometry showed markedly
        reduced abundance.
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared
        with WT
      explanation: Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
- name: Reduced cGKII Kinase Function
  role: intermediate
  biological_scale: MOLECULAR
  gene:
    preferred_term: PRKG2
    term:
      id: hgnc:9416
      label: PRKG2
  description: >-
    cGKII is a cGMP-dependent kinase downstream of CNP/NPR-B. Tested human variants fail to provide normal
    regulation of RAF/ERK signaling, while the rat mutant lacks a cGMP-stimulated kinase response. Loss of
    cGMP binding itself has not been demonstrated for every allele.
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared
      with WT
    explanation: Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
  - 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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The in vitro kinase assay revealed that the wild-type extract showed a significant increase in the kinase
      activity by the stimulation with the cGMP analog 8-bromo-cGMP; however, the increase was not observed
      in the KMI extract
    explanation: The cGMP-stimulated kinase response was absent in rat brain extracts.
  molecular_functions:
  - preferred_term: cGMP-dependent protein kinase activity
    term:
      id: GO:0004692
      label: cGMP-dependent protein kinase activity
    modifier: DECREASED
  downstream:
  - target: Persistent SOX9 Nuclear Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of cGKII permits persistent SOX9 nuclear localization and activity in rat and transfection systems.
      The molecular intermediary is unresolved; direct SOX9 S181/S64 phosphorylation is dispensable for this
      effect.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA
        level was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
      explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: the direct phosphorylation of Sox9 is dispensable for its attenuation by cGKII.
      explanation: Phosphorylation-deficient SOX9 remains responsive, ruling out the simple proposed bridge.
  - target: Reduced GSK3β Ser9 Phosphorylation
    causal_link_type: DIRECT
    description: >-
      Reduced cGKII removes phosphorylation input to GSK3β Ser9; recombinant-protein assays directly demonstrate
      that substrate reaction.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Direct phosphorylation of recombinant GSK-3β at Ser9, the crucial site for inactivation of GSK-3β (10),
        by recombinant cGKII protein was confirmed by in vitro kinase assay
      explanation: Direct biochemical evidence for the kinase-substrate step.
  - target: Reduced RAF1 Ser43 Phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the tested human-variant expression systems, impaired cGKII is associated with failure to induce RAF1
      Ser43 phosphorylation. Purified variant-enzyme/substrate kinetics were not measured.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Neither the V470G mutant nor R569* were able to phosphorylate c-RAF at Ser43
      explanation: Variant-transfection assays show loss of the measured phosphorylation response.
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss and re-expression experiments establish a contribution of cGKII to hypertrophic differentiation.
      The graph includes two experimentally supported contributing branches, without claiming that they exhaust
      its actions.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA
        level was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
      explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        the suppression of all of these differentiation markers in the KMI culture was restored to those similar
        to the wild-type culture
      explanation: Adenoviral cGKII complementation rescues rat-cell differentiation markers.
- name: Persistent SOX9 Nuclear Activity
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Persistent nuclear SOX9 and continued SOX9-dependent transcription contribute to impaired hypertrophic
    progression in the KMI rat. Cultured-cell SOX9 silencing rescues ALP and COL10 readouts. Nuclear exclusion
    is mechanistically separable from direct SOX9 phosphorylation and from the GSK3β branch.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA level
      was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
    explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      nuclear localization of Sox9 was clearly visible in the abnormal intermediate layer of the KMI growth
      plate
    explanation: In-vivo localization in the rat.
  downstream:
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistent SOX9 activity contributes to the differentiation defect, as supported by RNA-interference
      rescue in rat growth-plate chondrocytes.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA
        level was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
      explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
- name: Reduced GSK3β Ser9 Phosphorylation
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Prkg2-null mouse growth plates have reduced phospho-Ser9-GSK3β. Recombinant cGKII phosphorylates this inhibitory
    site directly. Persistence of GSK3β activity is the mechanistic interpretation; the paper did not directly
    measure degradation kinetics or all downstream substrates.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Direct phosphorylation of recombinant GSK-3β at Ser9, the crucial site for inactivation of GSK-3β (10),
      by recombinant cGKII protein was confirmed by in vitro kinase assay
    explanation: Direct biochemical evidence for the kinase-substrate step.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      cGKII deficiency caused similar decreases in β-catenin and Ser9- phosphorylated GSK-3β levels with little
      effect on the total GSK-3β level in the abnormal intermediate layer.
    explanation: Mouse growth-plate immunostaining shows the disease-direction change.
  downstream:
  - target: Reduced β-Catenin Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of inhibitory Ser9 phosphorylation is proposed to leave GSK3β-dependent β-catenin turnover less
      restrained. Cell-expression and S9A reporter experiments support this route, but turnover kinetics were
      not measured.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        using TOPflash and FOP- flash reporter plasmids in HEK293 cells transfected with constitutively active
        cGKII
      explanation: >-
        TCF reporter assays were in HEK293 cells; cytosolic β-catenin protein measurements were in ATDC5 cells.
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: which was markedly suppressed by cotransfection of GSK-3βS9A
      explanation: Phosphorylation-resistant GSK3β attenuates the cGKII-induced TCF reporter response in HEK293 cells.
    intermediate_mechanisms:
    - Persistent GSK3β activity
    - β-catenin turnover
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The GSK3β route contributes to delayed hypertrophy: S9A attenuates cGKII-induced markers in cells and
      Gsk3b haploinsufficiency partially rescues Prkg2-null mice. It is not the upstream mediator of SOX9 nuclear
      exclusion.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        Genetic rescue of impaired skeletal growth in Prkg2–/– mice by suppression of GSK-3 β was significant,
        but incomplete
      explanation: Partial genetic rescue supports contribution rather than sole mediation.
- name: Reduced β-Catenin Signaling
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Reduced β-catenin immunostaining is observed in Prkg2-null growth plates. cGKII constructs increase cytosolic
    β-catenin in ATDC5 cells and TCF reporter activity in HEK293 cells. These results support a candidate effector
    branch; β-catenin necessity for hypertrophic differentiation or rescue was not directly tested, and canonical
    Wnt-ligand activation was not established.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      using TOPflash and FOP- flash reporter plasmids in HEK293 cells transfected with constitutively active
      cGKII
    explanation: >-
      TCF reporter assays were in HEK293 cells; cytosolic β-catenin protein measurements were in ATDC5 cells.
  - 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: OTHER
    quote_role: BACKGROUND
    snippet: we note that there is no direct evidence of cGKII being involved in the canonical Wnt pathway.
    explanation: Authors explicitly limit the pathway interpretation.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      cGKII deficiency caused similar decreases in β-catenin and Ser9- phosphorylated GSK-3β levels with little
      effect on the total GSK-3β level in the abnormal intermediate layer.
    explanation: Mouse growth-plate immunostaining shows the disease-direction change.
  - 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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: which was markedly suppressed by cotransfection of GSK-3βS9A
    explanation: Phosphorylation-resistant GSK3β attenuates the cGKII-induced TCF reporter response in HEK293 cells.
- name: Reduced RAF1 Ser43 Phosphorylation
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    Human mutant cGKII constructs fail to induce normal RAF1 Ser43 phosphorylation in the cGMP/FGF2 assay.
    This phosphorylation readout is separated from downstream ERK activation.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Neither the V470G mutant nor R569* were able to phosphorylate c-RAF at Ser43
    explanation: Variant-transfection assays show loss of the measured phosphorylation response.
  downstream:
  - target: Persistent FGF2-Induced ERK Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The authors interpret reduced inhibitory RAF1 phosphorylation as the upstream explanation for failure
      to restrain the MAPK cascade. The expression experiments do not establish Ser43-specific necessity by
      a RAF1-site rescue.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Neither the V470G mutant nor R569* were able to phosphorylate c-RAF at Ser43
      explanation: Variant-transfection assays show loss of the measured phosphorylation response.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: >-
        the V470G mutant variant, as with the R569* positive control, was unable to down-regulate the MAPK
        pathway, as seen by the failure to reduce ERK1/2 activation
      explanation: The direction is clear in the complete functional results.
    intermediate_mechanisms:
    - RAF-MEK-ERK signaling
- name: Persistent FGF2-Induced ERK Activation
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    In HEK293T expression assays, R569*, D761Efs*34 and V470G fail to reduce FGF2-induced ERK1/2 activation
    as wild-type cGKII does. This is an experimentally measured signaling phenotype, not a patient growth-plate
    measurement. Its connection to the SOX9 branch has not been established by these variant assays.
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared
      with WT
    explanation: Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      the V470G mutant variant, as with the R569* positive control, was unable to down-regulate the MAPK pathway,
      as seen by the failure to reduce ERK1/2 activation
    explanation: The direction is clear in the complete functional results.
- name: Impaired Hypertrophic Chondrocyte Differentiation
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    Delayed transition from postmitotic to hypertrophic chondrocytes produces an abnormal intermediate growth-plate
    layer in rodent models. In rat primary cultures, ALP and COL10 are reduced and recover after cGKII expression
    or SOX9 silencing. Collagen measurements are context dependent: Angus mutant growth plates showed increased
    COL2 and COL10 RNA, so reduced COL10 is not universal across models.
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not started
      hypertrophic differentiation.
    explanation: Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
  - 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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA level
      was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
    explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Real-time PCR of COL10 indicated an increase in expression in dwarfs compared with normal individuals
    explanation: The cattle result limits generalization of the rat marker direction.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  downstream:
  - target: Impaired Endochondral Bone Growth
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disrupted growth-plate maturation compromises longitudinal endochondral bone growth. This tissue-level
      bridge is supported by rodent histology and bone-length phenotypes.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not started
        hypertrophic differentiation.
      explanation: Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: >-
        the longitudinal lengths of femora, tibiae, and vertebrae, all of which are formed through endochondral
        ossification, were 20%-30% shorter in KMI than in wild type
      explanation: Longitudinal skeletal growth defect in the rat model.
    intermediate_mechanisms:
    - Disordered growth-plate maturation and cartilage replacement
- name: Impaired Endochondral Bone Growth
  role: intermediate
  biological_scale: TISSUE
  description: >-
    Reduced endochondral growth shortens long bones and vertebrae in rodent models and provides the tissue-level
    explanation for the human skeletal growth disorder. The distribution and severity of human shortening vary,
    and model experiments do not explain each individual radiographic shape abnormality.
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      the longitudinal lengths of femora, tibiae, and vertebrae, all of which are formed through endochondral
      ossification, were 20%-30% shorter in KMI than in wild type
    explanation: Longitudinal skeletal growth defect in the rat model.
  biological_processes:
  - preferred_term: endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  downstream:
  - target: Disproportionate short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired growth-plate growth explains short-limb stature; applying model findings to the human distribution
      is a biological inference.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        the longitudinal lengths of femora, tibiae, and vertebrae, all of which are formed through endochondral
        ossification, were 20%-30% shorter in KMI than in wild type
      explanation: Longitudinal skeletal growth defect in the rat model.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: two girls with severe short stature due to acromesomelic limb shortening
      explanation: Human phenotype paired with the model-level mechanism.
  - target: Acromesomelic limb shortening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted endochondral growth contributes to middle/distal limb shortening when this presentation is
      present; some families lack obvious 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
      quote_role: PRIMARY_RESULT
      snippet: two girls with severe short stature due to acromesomelic limb shortening
      explanation: >-
        The human limb distribution is directly documented, while its detailed regional mechanism is inferred.
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced growth of digital bones can contribute to brachydactyly; neither its frequency nor the exact
      regional developmental explanation is established by the model experiments.
    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
      quote_role: PRIMARY_RESULT
      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: Human digital shortening associated with the same disorder.
phenotypes:
- name: Disproportionate short stature
  category: Skeletal
  description: >-
    Severity ranges from marked to moderate short stature. Acromesomelic disproportion may be mild or absent
    in a spondylometaphyseal presentation; worsening with age is documented in selected patients, not universal.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  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
    quote_role: PRIMARY_RESULT
    snippet: disproportionate short stature with notably short forearms and hands.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Acromesomelic limb shortening
  category: Skeletal
  description: >-
    Middle and distal limb shortening characterizes the founding cases, but is not present in every molecularly
    confirmed family.
  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
    quote_role: PRIMARY_RESULT
    snippet: two girls with severe short stature due to acromesomelic limb shortening
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Brachydactyly
  category: Skeletal
  description: >-
    Short hands and feet are common in reported acromesomelic presentations; some affected brothers had no
    hand shortening.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      The clinical findings included a prominent forehead, a broad chest, mild lumbar hyperlordosis, shortened
      forearms, mild brachydactyly of the hands and feet, relatively large and broad great toes and a sandal
      gap
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Platyspondyly
  category: Skeletal
  description: Vertebral flattening ranges from mild to prominent; it may 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
    quote_role: PRIMARY_RESULT
    snippet: platyspondyly with anterior beaking of the vertebral bodies
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Anterior vertebral beaking
  category: Skeletal
  description: Anterior projections or beaking accompany platyspondyly in several reported families.
  phenotype_term:
    preferred_term: Beaking of vertebral bodies
    term:
      id: HP:0004568
      label: Beaking of vertebral bodies
  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
    quote_role: PRIMARY_RESULT
    snippet: platyspondyly with anterior beaking of the vertebral bodies
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Metaphyseal widening
  category: Skeletal
  description: >-
    Metaphyseal flaring is variable and can evolve with age. Irregularity and striations are especially described
    at the distal radius and ulna; these are not all equivalent to widened metaphyses.
  phenotype_term:
    preferred_term: Metaphyseal widening
    term:
      id: HP:0003016
      label: Metaphyseal widening
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Radiological examination showed platyspondyly with anterior beaking of the vertebral bodies, stubby long
      bones with metaphyseal flaring
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Cone-shaped epiphyses
  category: Skeletal
  description: >-
    Cone-shaped phalangeal epiphyses occur in acromesomelic cases. Subtle distal phalangeal metaphyseal coning
    in the 2022 spondylometaphyseal family is a distinct observation.
  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
    quote_role: PRIMARY_RESULT
    snippet: moderate brachydactyly with cone-shaped epiphyses of the middle and proximal phalanges
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Limited elbow extension
  category: Skeletal
  description: Mild elbow-extension limitation was explicitly recorded in the first 2024 patient.
  phenotype_term:
    preferred_term: Limited elbow extension
    term:
      id: HP:0001377
      label: Limited elbow extension
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Generalized hirsutism, widening of wrists, mild limitation in elbow extension, and interphalangeal joint
      laxity were also noted.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Cubitus varus
  category: Skeletal
  description: Reported in the two brothers described in the natural-history study.
  phenotype_term:
    preferred_term: Cubitus varus
    term:
      id: HP:0025317
      label: Cubitus varus
  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
    quote_role: PRIMARY_RESULT
    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: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Radial bowing
  category: Skeletal
  description: Forearm radiographs in the first 2024 patient showed bowed radius and ulna.
  phenotype_term:
    preferred_term: Radial bowing
    term:
      id: HP:0002986
      label: Radial bowing
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Skeletal radiographs revealed platyspondyly with anterior beaking of thoracolumbar vertebral bodies,
      bowing of the radius and ulna, mild metaphyseal irregularities of the long bones, moderate brachydactyly
      and short and broad phalanges with cone-shaped epiphyses
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Ulnar bowing
  category: Skeletal
  description: Forearm radiographs in the first 2024 patient showed bowed ulna and radius.
  phenotype_term:
    preferred_term: Ulnar bowing
    term:
      id: HP:0003031
      label: Ulnar bowing
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Skeletal radiographs revealed platyspondyly with anterior beaking of thoracolumbar vertebral bodies,
      bowing of the radius and ulna, mild metaphyseal irregularities of the long bones, moderate brachydactyly
      and short and broad phalanges with cone-shaped epiphyses
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Finger joint hypermobility
  category: Musculoskeletal
  description: Interphalangeal joint laxity was recorded in the first 2024 patient.
  phenotype_term:
    preferred_term: Finger joint hypermobility
    term:
      id: HP:0006094
      label: Finger joint hypermobility
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Generalized hirsutism, widening of wrists, mild limitation in elbow extension, and interphalangeal joint
      laxity were also noted.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Lumbar hyperlordosis
  category: Skeletal
  description: Mild lumbar hyperlordosis occurs in the attenuated compound-heterozygous case.
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      The clinical findings included a prominent forehead, a broad chest, mild lumbar hyperlordosis, shortened
      forearms, mild brachydactyly of the hands and feet, relatively large and broad great toes and a sandal
      gap
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Thoracolumbar scoliosis
  category: Skeletal
  description: Recorded in the second 2024 patient.
  phenotype_term:
    preferred_term: Thoracolumbar scoliosis
    term:
      id: HP:0002944
      label: Thoracolumbar scoliosis
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      A skeletal survey showed mild mesomelia, thoracolumbar scoliosis, and subtle irregular metaphyseal changes.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Elongated femoral neck
  category: Skeletal
  description: Long, slender or biconcave femoral necks have been documented across more than one family.
  phenotype_term:
    preferred_term: Elongated femoral neck
    term:
      id: HP:0033985
      label: Elongated femoral neck
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: development of long, slender femoral necks.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Narrow femoral neck
  category: Skeletal
  description: Slender femoral necks accompany the elongated configuration in reported radiographs.
  phenotype_term:
    preferred_term: Narrow femoral neck
    term:
      id: HP:0008819
      label: Narrow femoral neck
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: development of long, slender femoral necks.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Short metacarpals
  category: Skeletal
  description: Metacarpal shortening was documented in the attenuated case and in the second 2024 patient.
  phenotype_term:
    preferred_term: Short metacarpal
    term:
      id: HP:0010049
      label: Short metacarpal
  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
    quote_role: PRIMARY_RESULT
    snippet: shortening of the metacarpals relative to the phalanges
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Metacarpal pseudoepiphyses
  category: Skeletal
  description: >-
    Incomplete first- and second-metacarpal pseudoepiphyses were reported in the attenuated case; this does
    not establish a recurrent feature.
  phenotype_term:
    preferred_term: Metacarpal pseudoepiphysis
    term:
      id: HP:0009193
      label: Metacarpal pseudoepiphysis
  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
    quote_role: PRIMARY_RESULT
    snippet: incomplete pseudo-epiphyses of the first and second metacarpals
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Broad hallux
  category: Skeletal
  description: >-
    Relatively large, broad great toes were directly described in the attenuated case; large halluces also
    appear in the 2024 report.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      The clinical findings included a prominent forehead, a broad chest, mild lumbar hyperlordosis, shortened
      forearms, mild brachydactyly of the hands and feet, relatively large and broad great toes and a sandal
      gap
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Sandal gap
  category: Skeletal
  description: Documented in the attenuated compound-heterozygous case.
  phenotype_term:
    preferred_term: Sandal gap
    term:
      id: HP:0001852
      label: Sandal gap
  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
    quote_role: PRIMARY_RESULT
    snippet: Feet demonstrating brachydactyly, large and broad great toes and a sandal gap.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Prominent fingertip pads
  category: Skeletal
  description: Fetal pads were noted with the mildly short fingers of the first 2024 patient.
  phenotype_term:
    preferred_term: Prominent fingertip pads
    term:
      id: HP:0001212
      label: Prominent fingertip pads
  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
    quote_role: PRIMARY_RESULT
    snippet: mildly short fingers with fetal pads
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Relative macrocephaly
  category: Head and neck
  description: Reported at nine months in the first 2024 patient, without requiring absolute macrocephaly.
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  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
    quote_role: PRIMARY_RESULT
    snippet: Relative macrocephaly and slow linear growth were noted at 9 months old.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Prominent forehead
  category: Head and neck
  description: Observed in both 2024 patients and the attenuated case.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Thick eyebrows
  category: Head and neck
  description: Observed in both 2024 patients; a syndrome-wide facial pattern remains preliminary.
  phenotype_term:
    preferred_term: Thick eyebrow
    term:
      id: HP:0000574
      label: Thick eyebrow
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Synophrys
  category: Head and neck
  description: Observed in both 2024 patients and retrospectively in several earlier photographs.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Wide nasal bridge
  category: Head and neck
  description: Broad nasal bridge was described in the two 2024 patients.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Anteverted nares
  category: Head and neck
  description: Explicitly described in the first 2024 patient.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Broad philtrum
  category: Head and neck
  description: Wide philtrum was explicitly described in the first 2024 patient.
  phenotype_term:
    preferred_term: Broad philtrum
    term:
      id: HP:0000289
      label: Broad philtrum
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      a prominent forehead, thick eyebrows, synophrys, broad nasal bridge, anteverted nares, and wide philtrum
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Long philtrum
  category: Head and neck
  description: Long philtrum was described in the second 2024 patient; length and width are separate observations.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  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
    quote_role: PRIMARY_RESULT
    snippet: anteverted nose, long philtrum and large halluces
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Generalized hypertrichosis
  category: Integument
  description: >-
    Generalized hirsutism/hypertrichosis was reported in the first 2024 patient and retrospectively in another
    case. The 2024 authors regard the overall facial/hair pattern as provisional.
  phenotype_term:
    preferred_term: Generalized hypertrichosis
    term:
      id: HP:0004554
      label: Generalized hypertrichosis
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Generalized hirsutism, widening of wrists, mild limitation in elbow extension, and interphalangeal joint
      laxity were also noted.
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Delayed skeletal maturation
  category: Skeletal
  description: >-
    Bone age was delayed by 1.5 years in the attenuated case; the second 2024 patient instead had advanced
    bone age.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  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
    quote_role: PRIMARY_RESULT
    snippet: a bone age delay of 1.5 years
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
- name: Accelerated skeletal maturation
  category: Skeletal
  description: >-
    Bone age was one year advanced in the second 2024 patient, demonstrating that skeletal maturation is not
    uniformly delayed.
  phenotype_term:
    preferred_term: Accelerated skeletal maturation
    term:
      id: HP:0005616
      label: Accelerated skeletal maturation
  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
    quote_role: PRIMARY_RESULT
    snippet: Her bone age was advanced by 1 year
    explanation: Direct observation in the cited patient or small case series; no disease-wide frequency is inferred.
animal_models:
- name: Prkg2-null mouse
  species: Mouse
  genotype: Prkg2−/−
  publication: PMID:12193576
  description: >-
    Global cGKII deficiency causes dwarfism and a disorganized, elongated growth plate. Growth-plate CNP overexpression
    fails to rescue the skeletal defect. Later detailed mouse work shows a postmitotic, poorly hypertrophic
    intermediate layer, with growth-plate expansion most evident at two to four weeks and persistent bone shortening
    after that expansion subsides.
  modeled_mechanisms:
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reproduces deficient growth-plate hypertrophic progression.
    limitations: >-
      A global null is more severe molecularly than some human alleles; the human regional pattern is not reproduced
      exactly.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral
        ossification
      explanation: Mouse knockout phenotype.
  - target: Impaired Endochondral Bone Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Prkg2 deficiency impairs skeletal growth, and growth-plate CNP overexpression does not rescue this defect.
    limitations: >-
      This is a global-null mouse experiment, not a human treatment trial; the skeletal-growth readout does
      not isolate a particular chondrocyte differentiation step.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral
        ossification
      explanation: The mouse model reproduces impaired endochondral skeletal growth.
    readouts:
    - name: Response to growth-plate CNP overexpression
      target: Impaired Endochondral Bone Growth
      direction: UNCHANGED
      interpretation: The upstream ligand did not rescue the skeletal growth defect in this null model.
      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
        quote_role: PRIMARY_RESULT
        snippet: >-
          targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of
          Prkg2(-/-) mice
        explanation: In-vivo negative rescue experiment.
- name: Prkg2-null mouse with Gsk3b haploinsufficiency
  species: Mouse
  genotype: Prkg2−/−; Gsk3b+/−
  publication: PMID:18551195
  description: >-
    Male compound-mutant mice show partial recovery of skeletal growth and growth-plate differentiation compared
    with Prkg2-null mice. Recovery is incomplete and refers to the deficit relative to wild type, not the proportion
    of normal bone length attained.
  modeled_mechanisms:
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    relationship: PERTURBS
    fidelity: MODERATE
    description: Genetic reduction of GSK3β partially ameliorates the differentiation/growth defect.
    limitations: >-
      Global Gsk3b dosage reduction does not isolate a chondrocyte-autonomous effect. Only male mice were studied;
      no human therapeutic efficacy was tested.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        Genetic rescue of impaired skeletal growth in Prkg2–/– mice by suppression of GSK-3 β was significant,
        but incomplete
      explanation: The compound-genetic experiment establishes contribution of the GSK3β route.
    readouts:
    - name: Excess growth-plate height
      target: Impaired Hypertrophic Chondrocyte Differentiation
      direction: RESTORED
      interpretation: >-
        The report quantified 36% recovery of the excessive growth-plate height, with partial COL10 restoration.
      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
        quote_role: PRIMARY_RESULT
        snippet: The percentage recovery by the GSK-3 β insufficiency was 36.0%.
        explanation: Quantified partial growth-plate rescue.
- name: Komeda miniature rat Ishikawa
  species: Rat
  genotype: Homozygous mri deletion spanning Prkg2 exons 4–5
  publication: PMID:15466490
  description: >-
    The naturally occurring approximately 5-kb deletion creates a frameshift and predicted kinase-domain truncation.
    Rats grow normally initially, then develop shortened limbs and trunk from about four weeks. Growth plates
    accumulate postmitotic nonhypertrophic cells; experimental tibial fracture healing is also delayed.
  modeled_mechanisms:
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Rat histology demonstrates the abnormal intermediate layer.
    limitations: >-
      The postnatal onset, fracture experiment and molecular readouts are model observations, not established
      human clinical complications.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not started
        hypertrophic differentiation.
      explanation: Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
    readouts:
    - name: Postmitotic nonhypertrophic growth-plate cells
      target: Impaired Hypertrophic Chondrocyte Differentiation
      direction: INCREASED
      interpretation: BrdU-negative, ALP/COL10-negative cells accumulate between proliferative and hypertrophic zones.
      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
        quote_role: PRIMARY_RESULT
        snippet: >-
          the intermediate layer chondrocytes were abnormal cells that had ceased proliferation but had not
          started hypertrophic differentiation.
        explanation: Rat histology distinguishes delayed differentiation from a hyperproliferative layer.
  - target: Persistent SOX9 Nuclear Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: SOX9 persists in nuclei of the abnormal intermediate layer.
    limitations: >-
      Localization alone does not establish the intermediary; the causal silencing experiment was performed
      in isolated cells.
    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
      quote_role: PRIMARY_RESULT
      snippet: >-
        nuclear localization of Sox9 was clearly visible in the abnormal intermediate layer of the KMI growth
        plate
      explanation: Direct rat immunolocalization.
- name: Angus cattle with PRKG2 R678X
  species: Cattle
  genotype: Homozygous PRKG2 p.Arg678Ter
  publication: PMID:19887637
  description: >-
    A naturally occurring recessive nonsense variant cosegregated with dwarfism. The experimental breeding
    cohort comprised four homozygous affected calves and two heterozygous unaffected calves studied around
    seven months; long bones and stature were reduced. Growth-plate COL2 and COL10 RNA both increased, while
    total PRKG2 RNA did not differ detectably.
  modeled_mechanisms:
  - target: Impaired Endochondral Bone Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Naturally occurring disruption of the homologous gene produces impaired skeletal growth.
    limitations: >-
      Small cohort with heterozygous controls and shared ancestry. Its increased COL10 RNA differs from reduced
      COL10 in rat-cell experiments; no universal collagen-X direction or human fracture risk follows.
    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
      quote_role: PRIMARY_RESULT
      snippet: Animals predicted to be dwarfs by the R678X PRKG2 marker had shorter metatarsals
      explanation: Direct bone-length phenotype in the breeding cohort.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: Real-time PCR of COL10 indicated an increase in expression in dwarfs compared with normal individuals
      explanation: Measured cattle growth-plate RNA.
- name: Dogo Argentino PRKG2 splice-site candidate
  species: Dog
  genotype: Homozygous PRKG2 c.1634+1G>T
  publication: PMID:34680883
  description: >-
    Two affected half-siblings in a nine-dog family had disproportionate dwarfism. Detailed radiography and
    CT of the male showed forelimb deformity, premature distal ulnar physeal closure and impaired endochondral
    ossification. The splice-donor variant cosegregated with the phenotype and was prioritized against 795
    control genomes.
  modeled_mechanisms:
  - target: Impaired Endochondral Bone Growth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Comparative genetic evidence links the candidate splice defect to abnormal skeletal growth.
    limitations: >-
      No patient-derived RNA, protein or kinase assay established splice loss in the dogs; the variant remains
      a strongly supported candidate in this report. The detailed imaging was from one affected male.
    evidence:
    - reference: PMID:34680883
      reference_title: PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family
        of dogs.
      explanation: Family segregation supports the candidate association.
experimental_models:
- name: Human PRKG2 variants in HEK293T cells
  experimental_model_type: CELL_LINE
  publication: PMID:34782440
  description: >-
    Transient expression compared human WT cGKII with R569*, D761Efs*34 and, in a later study, V470G. Cells
    were challenged with a cGMP analog and FGF2; immunoblots measured cGKII abundance, RAF1 Ser43 phosphorylation
    and ERK1/2 activation. The studies used three biological experiments for their signaling comparisons.
  modeled_mechanisms:
  - target: Reduced cGKII Protein Abundance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Human mutant constructs yield reduced protein abundance.
    limitations: >-
      Overexpression does not measure endogenous patient protein levels or distinguish synthesis from turnover.
    evidence:
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: For both variants, cGKII was detected at the predicted size
      explanation: >-
        Immunoblotting detected the R569* and D761Efs*34 proteins; subsequent densitometry showed markedly
        reduced abundance.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: The mutant cGKII protein levels were severely reduced compared to wild-type cGKII.
      explanation: Later V470G result.
  - target: Reduced RAF1 Ser43 Phosphorylation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Mutants fail to induce RAF1 Ser43 phosphorylation.
    limitations: The assay does not independently establish purified-enzyme kinetics or RAF1-site necessity.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Neither the V470G mutant nor R569* were able to phosphorylate c-RAF at Ser43
      explanation: Variant-transfection assays show loss of the measured phosphorylation response.
  - target: Persistent FGF2-Induced ERK Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Mutants fail to restrain FGF2-induced ERK1/2 activation.
    limitations: >-
      HEK293T cells are not growth-plate chondrocytes; this does not directly connect ERK activation to SOX9
      or patient cartilage behavior.
    evidence:
    - reference: PMID:34782440
      reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared
        with WT
      explanation: Functional deficit in transient-expression assays. This is not a purified-kinase kinetic assay.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: >-
        the V470G mutant variant, as with the R569* positive control, was unable to down-regulate the MAPK
        pathway, as seen by the failure to reduce ERK1/2 activation
      explanation: The direction is clear in the complete functional results.
- name: PRKG2 family fibroblast RNA analysis
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:41574272
  cell_source: Dermal fibroblasts from the proband, parents and a healthy control
  description: >-
    RT-PCR and targeted cDNA sequencing examined the two compound-heterozygous alleles. The carrier father
    had two c.1630G>T-bearing RNA populations, and the carrier mother showed marked depletion of c.1074del-bearing
    RNA. The paper predicts protein consequences and a hypomorphic mechanism but does not measure those proteins
    or their kinase activity.
  modeled_mechanisms:
  - target: Aberrant PRKG2 Splicing
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Demonstrates use of a cryptic exon-13 donor.
    limitations: >-
      The approximately half-spliced estimate is reported from the carrier father; no patient chondrocyte experiment
      was performed.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Analysis of the proband’s father revealed aberrant transcripts, which were absent in controls and characterized
        by a 6-nucleotide truncation of exon 13
      explanation: Carrier fibroblast RNA establishes the splice consequence of c.1630G>T.
  - target: PRKG2 Transcript Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Shows a 92:8 wild-type:mutant ratio for the maternal frameshift allele.
    limitations: >-
      Allelic imbalance is consistent with decay but is not a transcript half-life or NMD-inhibitor rescue
      measurement.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: revealed a significant allelic imbalance (wt/mut ratio = 92/8)
      explanation: Measured maternal allelic RNA imbalance.
- name: KMI rat growth-plate chondrocyte cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:15466490
  cell_source: Primary tibial growth-plate chondrocytes from wild-type and KMI rats
  description: >-
    Cultures reproduce deficient ALP and COL10 induction without a significant difference in proliferation.
    Adenoviral cGKII expression and SOX9 RNA interference rescue differentiation readouts. CNP fails to rescue
    the mutant-cell response, whereas BMP2 stimulates differentiation markers.
  modeled_mechanisms:
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Primary mutant cells reproduce and permit rescue of the differentiation defect.
    limitations: Culture rescue is not a demonstrated in-vivo treatment.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA
        level was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
      explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        the suppression of all of these differentiation markers in the KMI culture was restored to those similar
        to the wild-type culture
      explanation: Adenoviral complementation result.
    readouts:
    - name: ALP and COL10 after SOX9 silencing
      target: Impaired Hypertrophic Chondrocyte Differentiation
      direction: RESTORED
      interpretation: Silencing reverses the selected deficient differentiation readouts.
      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: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          The impaired differentiation of KMI chondrocytes determined by the ALP staining and the COL10 mRNA
          level was reversed by the retrovirus-mediated introduction of Sox9 RNAi.
        explanation: Silencing rescue supports a causal contribution of SOX9 in rat chondrocytes.
  - target: Persistent SOX9 Nuclear Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: cGMP or CNP excludes SOX9 from the nucleus in wild-type but not KMI cells.
    limitations: The intermediary remains unknown.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Treatment with the cGMP analog 8-bromo-cGMP inhibited nuclear entry of Sox9 in wild-type cells, whereas
        it did not in KMI cells.
      explanation: Primary-cell localization result.
- name: SOX9 localization and transcription assays
  experimental_model_type: CELL_LINE
  publication: PMID:15466490
  cell_source: HeLa localization assays, HuH-7 COL2 expression assays, and ATDC5 hypertrophic cultures
  description: >-
    cGKII expression alters SOX9 localization and SOX9-dependent collagen readouts. Phosphorylation-deficient
    SOX9 and forced nuclear-localization constructs distinguish nuclear entry from direct SOX9 phosphorylation.
    The cell systems and readouts differ and are not pooled as one chondrocyte experiment.
  modeled_mechanisms:
  - target: Persistent SOX9 Nuclear Activity
    relationship: PERTURBS
    fidelity: MODERATE
    description: Engineered localization and transcription assays dissect the SOX9 contribution.
    limitations: HeLa and HuH-7 are heterologous cells; COL2/COL10 readouts are not patient-cartilage measurements.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: the direct phosphorylation of Sox9 is dispensable for its attenuation by cGKII.
      explanation: Phosphosite-mutant evidence limits the direct phosphorylation model.
- name: cGKII–GSK3β biochemical and cell experiments
  experimental_model_type: OTHER
  publication: PMID:18551195
  cell_source: Purified recombinant proteins; ATDC5, HEK293, HuH-7 and primary mouse chondrocytes
  description: >-
    Recombinant kinase assays establish GSK3β Ser9 phosphorylation. ATDC5 and primary chondrocyte experiments
    examine hypertrophic markers; ATDC5 measures cytosolic β-catenin, while HEK293 hosts TCF reporters and
    Axin co-immunoprecipitation. Constitutively active cGKII and phosphorylation-resistant GSK3β S9A probe
    pathway function. LiCl is a laboratory perturbation, not an established AMDP therapy.
  modeled_mechanisms:
  - target: Reduced GSK3β Ser9 Phosphorylation
    relationship: PERTURBS
    fidelity: MODERATE
    description: Purified proteins directly establish the phosphorylation step.
    limitations: >-
      Ser9 biology and functional S9A experiments support inactivation; the assay does not directly measure
      every downstream GSK3β reaction.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Direct phosphorylation of recombinant GSK-3β at Ser9, the crucial site for inactivation of GSK-3β (10),
        by recombinant cGKII protein was confirmed by in vitro kinase assay
      explanation: Direct biochemical evidence for the kinase-substrate step.
  - target: Reduced β-Catenin Signaling
    relationship: PERTURBS
    fidelity: MODERATE
    description: cGKII increases β-catenin abundance and TCF activity in different cell systems.
    limitations: >-
      No β-catenin loss-of-function epistasis establishes its necessity for hypertrophy, and Axin co-immunoprecipitation
      is not purified pairwise binding.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        using TOPflash and FOP- flash reporter plasmids in HEK293 cells transfected with constitutively active
        cGKII
      explanation: >-
        TCF reporter assays were in HEK293 cells; cytosolic β-catenin protein measurements were in ATDC5 cells.
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: which was markedly suppressed by cotransfection of GSK-3βS9A
      explanation: Phosphorylation-resistant GSK3β attenuates the cGKII-induced TCF reporter response in HEK293 cells.
  - target: Impaired Hypertrophic Chondrocyte Differentiation
    relationship: PERTURBS
    fidelity: MODERATE
    description: Phosphorylation-resistant GSK3β attenuates the cGKII-induced hypertrophic markers.
    limitations: >-
      Gsk3b+/− primary cells increased COL10 but not ALP or MMP13; marker effects are not identical across
      experiments.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient
        mutant of GSK-3beta.
      explanation: Functional interference with the proposed GSK3β contribution.
- name: Bovine R678X cGKII in HuH-7 cells
  experimental_model_type: CELL_LINE
  publication: PMID:19887637
  description: >-
    Human hepatoma cells expressed bovine wild-type or R678X cGKII together with human SOX9. The mutant failed
    to suppress COL2 RNA to the level seen with wild-type cGKII.
  modeled_mechanisms:
  - target: Persistent SOX9 Nuclear Activity
    relationship: PERTURBS
    fidelity: MODERATE
    description: Tests a SOX9-dependent transcriptional consequence of the cattle allele.
    limitations: >-
      Not a bovine primary chondrocyte culture, direct localization assay, or human pathogenic-variant experiment.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Cells transfected with the R678X btPRKG2 vector had a 38% increase in COL2 mRNA compared with cells transfected
        with WT btPRKG2
      explanation: Direct relative COL2 expression result in heterologous cells.
- name: Patient-derived IGIBi007-A iPSC resource
  experimental_model_type: CELL_LINE
  publication: PMID:33887582
  cell_source: Reprogrammed patient lymphoblastoid cell line carrying p.Asn164Lysfs*2
  description: >-
    The reported iPSC line retained pluripotency and trilineage differentiation capacity without major reprogramming-related
    genetic alterations. It is a resource for future cartilage and treatment studies; the cited abstract does
    not report differentiated chondrocyte phenotypes or therapeutic rescue.
  evidence:
  - reference: PMID:33887582
    reference_title: >-
      Generation of induced pluripotent stem cell line (IGIBi007-A) from a patient with a novel acromesomelic
      dysplasia, PRKG2 type (AMDP).
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      We report generation of induced pluripotent stem cell line from lymphoblastoid cell lines of the patient
      carrying the reported frameshift mutation (p.Asn164Lysfs*2).
    explanation: Resource derivation is reported, not a completed skeletal-mechanism experiment.
diagnosis:
- name: Clinical and radiographic assessment with molecular confirmation
  description: >-
    Evaluate disproportionate growth and limb, hand, femoral-neck and spinal findings. A predominantly spondylometaphyseal
    presentation does not exclude PRKG2 disease. Exome or genome analysis can identify biallelic variants;
    segregation and, where needed, variant-specific RNA or functional studies help interpretation. A negative
    older panel can reflect omission of PRKG2.
  evidence:
  - reference: PMID:34782440
    reference_title: Variable skeletal phenotypes associated with biallelic variants in PRKG2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: WGS and subsequent Sanger sequencing uncovered a homozygous pathogenic PRKG2 variant
    explanation: Genome sequencing and confirmation in the spondylometaphyseal family.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Initial DNA diagnostics using a skeletal dysplasia gene panel (166 genes) failed to identify causative
      variants.
    explanation: The text attributes the negative panel to the gene not being included at that time.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: This variant leads to the production of two aberrant transcript populations
    explanation: RNA analysis clarifies a coding variant with an additional splice effect.
- name: Assessment of growth and skeletal maturation
  description: >-
    Endocrine and growth assessment complements skeletal imaging. Normal IGF-1 and other routine endocrine
    results occurred in reported cases; normal results do not exclude this primary skeletal disorder. Bone
    age may be delayed or advanced, so neither direction is a required diagnostic criterion.
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      Levels of TSH, free T4, IGF-1, parathyroid hormone, ionized calcium, and 25-hydroxyvitamin D were within
      the normal range.
    explanation: Normal biochemical screening in one affected child.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The hormonal evaluation showed a normal IGF-1
    explanation: Normal IGF-1 in another molecularly diagnosed child.
treatments:
- name: Reported growth hormone treatment
  description: >-
    Growth hormone was initiated at age six in the first patient in the 2024 report. This is an individual
    treatment exposure, not evidence of efficacy or a disorder-specific recommendation; the report provides
    no treatment response or dose.
  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
    quote_role: PRIMARY_RESULT
    snippet: GH treatment was started at the age of six.
    explanation: >-
      The paper reports treatment initiation in one patient but supplies no dose, subsequent height outcome
      or adverse-event assessment.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Growth hormone treatment
    term:
      id: NCIT:C15445
      label: Hormone Therapy
    therapeutic_agent:
    - preferred_term: growth hormone
      term:
        id: NCIT:C164163
        label: Therapeutic Growth Hormone
  target_mechanisms:
  - target: Disproportionate short stature
    description: >-
      The reported treatment was aimed at growth impairment. No direction or magnitude of treatment response
      is assigned because the paper reports initiation only.
    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
      quote_role: PRIMARY_RESULT
      snippet: GH treatment was started at the age of six.
      explanation: >-
        The paper reports treatment initiation in one patient but supplies no dose, subsequent height outcome
        or adverse-event assessment.
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 generalized cone-shaped epiphyses with phalangeal shortening are characteristic of AMDM. In
    the PRKG2 family presenting as spondylometaphyseal dysplasia, the subtle coning involved distal phalangeal
    metaphyses and was unaccompanied by shortening; these are anatomically distinct observations.
  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.
- name: Hypochondroplasia
  description: >-
    The attenuated compound-heterozygous case was initially suspected to have hypochondroplasia before negative
    FGFR3 testing and subsequent identification of PRKG2 variants.
  distinguishing_features:
  - >-
    The PRKG2 presentation may include mild forearm and digital shortening with slender elongated femoral necks.
    Molecular testing distinguishes the conditions; the report does not define a validated radiographic decision
    rule.
  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
    quote_role: PRIMARY_RESULT
    snippet: >-
      hypochondroplasia was initially suspected. However, no pathogenic variants in the FGFR3 gene were identified.
    explanation: Directly documents the diagnostic overlap.
mechanistic_hypotheses: []
discussions:
- kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced cGKII Kinase Function
  prompt: How do residual kinase function and tissue-specific effects explain severity across PRKG2 alleles?
  rationale: >-
    The attenuated compound-heterozygous case has direct RNA evidence, but the proposed residual function of
    its missense/in-frame-deletion products was not measured. The D761Efs*34 family has a predominantly spondylometaphyseal
    phenotype despite marked signaling defects in heterologous cells. These reports do not establish a quantitative
    genotype–phenotype rule.
  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: OTHER
    quote_role: BACKGROUND
    snippet: >-
      We hypothesize that these alterations cause a partial, rather than complete, loss of protein function
    explanation: The source explicitly presents hypomorphism as a hypothesis.
  discussion_id: residual_function
- kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced cGKII Kinase Function
  - pathophysiology#Impaired Endochondral Bone Growth
  prompt: Which interventions improve growth or function in molecularly confirmed PRKG2 disease?
  rationale: >-
    The reported growth-hormone exposure has no published outcome in that case report. CNP overexpression fails
    to rescue the Prkg2-null mouse, but this is not a human vosoritide trial and cannot settle responses of
    all partially functional alleles. The phase II vosoritide basket study included RASopathies, ACAN variants
    and heterozygous NPR2 variants, not PRKG2 disease; its efficacy cannot be transferred to this diagnosis.
  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
    quote_role: PRIMARY_RESULT
    snippet: GH treatment was started at the age of six.
    explanation: >-
      The paper reports treatment initiation in one patient but supplies no dose, subsequent height outcome
      or adverse-event assessment.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: >-
      targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-)
      mice
    explanation: Relevant negative model rescue, with an explicit limit on clinical extrapolation.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Carriers of heterozygous pathogenic/likely pathogenic variants in NPR2
    explanation: The basket-trial eligibility concerned the upstream receptor in heterozygous cases, not PRKG2.
  discussion_id: treatment_response
- kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Persistent SOX9 Nuclear Activity
  - pathophysiology#Reduced GSK3β Ser9 Phosphorylation
  - pathophysiology#Reduced β-Catenin Signaling
  - pathophysiology#Reduced RAF1 Ser43 Phosphorylation
  - pathophysiology#Persistent FGF2-Induced ERK Activation
  - pathophysiology#Impaired Hypertrophic Chondrocyte Differentiation
  prompt: >-
    How do the measured RAF/ERK, SOX9 and GSK3β-related effects combine in patient growth-plate chondrocytes?
  rationale: >-
    The human-variant RAF/ERK assays are heterologous expression experiments. Rodent and engineered-cell studies
    support SOX9 and GSK3β contributions, but do not place GSK3β upstream of SOX9 exclusion or prove β-catenin
    necessity. Direct SOX9 phosphorylation is dispensable for the localization effect. The ERK assay direction
    is established; the unresolved issue is mediation and integration in the relevant human tissue.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Neither addition of the GSK-3β inhibitor LiCl nor overexpression of GSK-3 βS9A altered cGKII-dependent
      inhibition of Sox9 nuclear entry
    explanation: The tested GSK3β manipulations did not mediate SOX9 localization.
  discussion_id: signaling_integration
notes: >-
  The 2022 middle brother with recurrent fractures, blue sclerae and osteopenia also had a de novo COL1A1 frameshift
  causing osteogenesis imperfecta; those findings are not assigned to PRKG2 disease here. Clinical evidence
  consists of small, selected families and cases, so no pooled phenotype frequencies are assigned. No PRKG2-specific
  GeneReviews or StatPearls chapter was identified in the repository inventories. There is no matching disorder-specific
  deep-research report; relevant PRKG2 passages in the related Maroteaux report were checked against primary
  literature. Full-text clinical studies and model papers were read, including the retrieved 2004 rat and 2024
  clinical articles; the founding 2020/2022 report, 2023 sibling study, 2002 CNP study, 2005 ATDC5 study and
  2021 iPSC report remain abstract-limited after retrieval attempts. The attempted institutional 2002 scan
  had no extractable cached text and the thesis contained only a citation to the founding study; neither is
  cited. Supplemental files were not independently reviewed. Source- and model-specific limitations are retained
  at the relevant claims.