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Parastremmatic dysplasia is a rare, dominantly inherited skeletal dysplasia characterized by severe short stature, progressive deformities of long tubular bones, and axial skeleton anomalies. It belongs to the TRPV4 skeletal dysplasia spectrum, which includes brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, and Maroteaux-type spondylo-epiphyseal dysplasia (PMID:20503319). Clinical-radiographic phenotypes vary widely, reflecting the pleiotropic effects of TRPV4 channel dysfunction on chondrogenesis and skeletal maturation. Parastremmatic dysplasia was recently linked to TRPV4 following targeted sequencing in a cohort including six SED Maroteaux type patients and one parastremmatic dysplasia patient. In this study, heterozygous mutations affecting the TRPV4 channel pore and regulatory domains were identified across affected individuals. These findings establish parastremmatic dysplasia as part of the TRPV4 dysplasia family with an autosomal dominant inheritance pattern.
Genetic analyses of seven unrelated probands with TRPV4-related skeletal dysplasias reported heterozygous missense and frameshift variants, supporting a dominant mechanism (PMID:20503319). The parastremmatic dysplasia patient harbored the recurrent TRPV4 c.1781G>A (p.Arg594His) variant, previously associated with SMDK and seen in multiple individuals. No additional family segregation was reported for parastremmatic dysplasia, but de novo occurrence is likely given the absence of parental phenotypes. Variant types include missense substitutions clustering in the channel pore (e.g., p.Arg594His) and N-terminal regulatory domains. Hotspot residues such as Arg594 and Pro799 underline genotype–phenotype correlations across the TRPV4 dysplasia spectrum. Collectively, these data provide strong genetic evidence for TRPV4 in parastremmatic dysplasia.
Functional studies demonstrate that TRPV4 dysplasia-causing mutations often result in gain-of-function channel activity, with increased Ca2+ permeability and constitutive opening. Mutants in the pore region, including R594H, show enhanced basal currents and elevated intracellular calcium influx, consistent with skeletal dysplasia pathogenesis. Glycosylation assays of TRPV4(N651Q) revealed that post-translational modifications modulate membrane trafficking and channel responsiveness (PMID:16368742). Ankyrin domain interactions are essential for subunit multimerization and surface expression, as shown by analyses of ARD-deleted splice variants (PMID:16293632). Structural studies of disease-associated ARD mutations indicate altered stability and disrupted ATP or calmodulin binding, supporting a gain-of-function or altered regulation mechanism. Overall, experimental evidence from cellular models converges on dysregulated TRPV4 channel biogenesis and function in skeletal dysplasia.
To date, no reports have refuted the role of TRPV4 in parastremmatic dysplasia, but variability in phenotypic expressivity suggests additional modifiers. Some TRPV4 variants associated with neuropathies display loss-of-function phenotypes, highlighting domain-specific functional consequences. Comprehensive neuropathy screens identified non-pathogenic TRPV4 variants in<1% of patients, underscoring the need for thorough functional validation (PMID:22851605). The interplay between TRPV4 and ancillary proteins such as ZC4H2 and STIM1 modulates channel turnover and activity, which may influence clinical severity. These insights suggest that both intrinsic channel properties and extrinsic regulators contribute to TRPV4-related phenotypic diversity. Future analyses integrating genotype, functional assays, and patient phenotypes are required to refine clinical correlations.
In summary, dominant heterozygous TRPV4 variants, particularly c.1781G>A (p.Arg594His), underlie a spectrum of skeletal dysplasias that encompasses parastremmatic dysplasia. Genetic data from seven probands and extensive experimental concordance establish a strong clinical validity for TRPV4 in this disorder. Autosomal dominant inheritance with recurrent de novo variants and clear functional impact on channel activity support diagnostic testing. Functional assays have elucidated gain-of-function mechanisms, including dysregulated glycosylation, trafficking, and enhanced Ca2+ influx. No conflicting evidence specific to parastremmatic dysplasia has emerged, although TRPV4 channelopathies display domain-dependent gain- or loss-of-function effects in other tissues. Incorporation of TRPV4 sequencing and functional studies will improve diagnostic accuracy and inform therapeutic strategies. Key Take-home: TRPV4 variant analysis is clinically actionable for diagnosing and managing parastremmatic dysplasia.
Gene–Disease AssociationStrong7 probands including one parastremmatic dysplasia patient and six Maroteaux-type SED patients with de novo heterozygous TRPV4 mutations (PMID:20503319), recurrent p.Arg594His variant and functional concordance Genetic EvidenceStrongRecurrent de novo heterozygous c.1781G>A (p.Arg594His) in parastremmatic dysplasia patient and six SED Maroteaux type probands; autosomal dominant inheritance Functional EvidenceModerateMultiple in vitro studies demonstrate TRPV4 mutant channel gain-of-function, altered glycosylation, trafficking, and ARD interactions consistent with disease pathogenesis |