TRPV3 – Olmsted Syndrome

TRPV3 has been robustly implicated in Olmsted syndrome, a rare genodermatosis characterized by severe palmoplantar keratoderma and periorificial hyperkeratotic plaques. Multiple independent studies, including both de novo cases and familial occurrences, have identified heterozygous missense variants in TRPV3, reinforcing an autosomal dominant pattern of inheritance in most patients (PMID:24452206, PMID:24758389). In several reports, approximately 50 cases have been documented, with recurrent mutations observed across unrelated probands and segregation of mutant alleles in affected families (PMID:22405088).

Genetic evidence supporting this association is strong. In one definitive case, a novel heterozygous missense mutation, c.2017C>T (p.Leu673Phe), was identified in a patient with classic Olmsted syndrome features (PMID:24452206). Additional case series and multi‐patient studies have detected several unique and recurrent variants, with some families demonstrating segregation of the variant with the disease phenotype, thereby bolstering the genotype–phenotype correlation (PMID:32795529).

Functional studies further support the role of TRPV3 in the pathogenesis of Olmsted syndrome. In vitro experiments and animal models demonstrate that these variants, predominantly gain‑of‑function in nature, lead to constitutive channel activation. Such aberrant channel activity has been shown to disturb ion homeostasis and promote keratinocyte apoptosis, culminating in the hyperkeratotic lesions that define the disease (PMID:17706768, PMID:28391651). Rescue experiments using specific inhibitors like erlotinib have also yielded positive outcomes, reinforcing the therapeutic potential of targeting this pathway (PMID:39926429).

Although there is a reported case of compound heterozygosity suggesting an autosomal recessive mechanism, the overwhelming majority of data supports an autosomal dominant inheritance for TRPV3‐related Olmsted syndrome. This heterogeneity in inheritance patterns may reflect differential effects of specific variants on channel function, yet the core pathogenic mechanism remains a gain‑of‑function disturbance, as evidenced by both in vitro and in vivo studies.

The aggregation of genetic and functional evidence leads to a coherent narrative where recurrent TRPV3 mutations provoke a constitutive activation of the channel, resulting in the distinctive cutaneous manifestations of Olmsted syndrome. In addition to the primary genetic evidence, the functional assays reliably recapitulate the human phenotype, thus underscoring the utility of TRPV3 as a diagnostic marker and potential therapeutic target.

Key take‑home: Comprehensive evaluation of TRPV3 mutations in Olmsted syndrome supports its clinical utility as a diagnostic and therapeutic target, with strong genetic and experimental evidence grounding its role in disease pathogenesis.

References

• Orphanet journal of rare diseases • 2013 • Olmsted syndrome: exploration of the immunological phenotype PMID:23692804
• JAMA dermatology • 2014 • A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia PMID:24452206
• Clinical and experimental dermatology • 2014 • Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3 PMID:24758389
• The Journal of dermatology • 2017 • Identification of a heterozygous p.Gly568Val missense mutation in the TRPV3 gene in a Japanese patient with Olmsted syndrome: In silico analysis of TRPV3 PMID:28391651
• American journal of human genetics • 2012 • Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome PMID:22405088
• Frontiers in medicine • 2025 • Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report PMID:39926429
• International journal of trichology • 2016 • Olmsted Syndrome in a Family PMID:28442872
• The Journal of investigative dermatology • 2021 • Genotype‐Phenotype Correlation of TRPV3‐Related Olmsted Syndrome PMID:32795529

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