TRPV4 – Scapuloperoneal Spinal Muscular Atrophy

Transient receptor potential cation channel subfamily V member 4 (TRPV4) is definitively associated with autosomal dominant scapuloperoneal spinal muscular atrophy (SPSMA). Affected individuals present with progressive scapular and peroneal muscle atrophy, often accompanied by vocal cord paralysis (HP:0001605), scoliosis (HP:0002650), arthrogryposis multiplex congenita (HP:0002804), and skeletal dysplasia (HP:0002652).

SPSMA follows an autosomal dominant pattern with heterozygous TRPV4 missense variants. Initial locus mapping and mutation discovery in two large pedigrees established allelism with Charcot–Marie–Tooth disease type 2C at 12q24 and identified TRPV4 as the causal gene (PMID:20037587). Subsequent screening of hereditary neuropathy cohorts revealed eight unrelated families with co-segregation of TRPV4 variants in 19 affected relatives (PMID:20460441).

In a series of 169 patients with axonal neuropathy plus vocal cord paralysis and/or skeletal dysplasia, 12 of 74 individuals (16%) harbored SPSMA-linked TRPV4 mutations, including de novo and familial events across diverse ethnicities (PMID:24789864). Reported pathogenic alleles affecting conserved residues include c.806G>A (p.Arg269His), c.805C>T (p.Arg269Cys), and c.946C>T (p.Arg316Cys), underscoring recurrent targeting of the ankyrin repeat domain.

The variant spectrum is dominated by heterozygous missense changes at conserved arginine hotspots within the ankyrin repeat domain, with no clear founder mutations, reflecting independent mutational events in each pedigree.

Functional assays demonstrate that SPSMA-associated TRPV4 mutants exhibit increased constitutive and stimulated calcium influx, higher open probability, and cytotoxicity in heterologous cells, consistent with a gain-of-function pathogenic mechanism (PMID:21454511). These findings align with altered channel gating observed across multiple in vitro studies.

Although TRPV4 variants are rare in “pure” CMT2 cohorts, reduced penetrance and variable expressivity have been reported, highlighting the importance of clinical correlation. The robust genetic segregation, recurrent identification of missense alleles, and concordant functional data establish a Definitive gene-disease relationship. Early genetic diagnosis enables targeted monitoring of respiratory and orthopedic complications and informs family counseling.

References

• Nature Genetics • 2010 • Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. PMID:20037587
• Brain • 2010 • Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. PMID:20460441
• Neurology • 2014 • Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. PMID:24789864
• Neuromuscular disorders • 2016 • TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature. PMID:26948711
• The Journal of Biological Chemistry • 2011 • Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. PMID:21454511

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