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Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis characterized by an abnormal susceptibility to cutaneous β-human papillomavirus (HPV) infections and a high risk of non-melanoma skin cancers. The TMC6 gene (formerly EVER1) encodes an endoplasmic reticulum transmembrane protein that regulates intracellular zinc distribution in concert with ZnT-1. Loss-of-function variants in TMC6 disrupt keratinocyte and lymphocyte zinc homeostasis, predisposing to persistent EV HPV infection and carcinogenesis.
Biallelic TMC6 null variants have been identified in >250 probands across >20 unrelated families, all exhibiting autosomal recessive inheritance and robust segregation with disease ((PMID:28646613)). The spectrum includes nonsense, frameshift, splice-site and large intragenic deletions, consistent with a loss-of-function mechanism. One recurrent variant is c.280C>T (p.Arg94Ter), detected in multiple cohorts and absent from control databases.
Case reports further illustrate allelic diversity and segregation. A Japanese patient harbored compound heterozygous c.744C>A (p.Tyr248Ter) and IVS8-2A>T in TMC6 ((PMID:15042430)). An Indian family exhibited a homozygous 2078 bp deletion (c.2072_2278del) in two affected siblings, with carrier parents and unaffected siblings segregating accordingly ((PMID:38574087)). In a Chinese pedigree, a homozygous splice acceptor variant c.2278-2A>G resulted in exon skipping and mRNA decay in the sole proband ((PMID:34386043)).
Functional studies support haploinsufficiency as the disease mechanism. In vitro, EVER1/TMC6 and EVER2 form a complex with ZnT-1 that controls zinc flux to nucleoli and down-regulates zinc- and cytokine-responsive transcription factors; pathogenic variants abolish this regulation ((PMID:18158319)). In lymphocytes, TMC6 interacts with TMC8 and CIB1 to form a heterotrimer that stabilizes each component; deficiency reduces complex formation, implicating immune dysfunction in EV pathogenesis ((PMID:32917726)).
Despite compelling evidence, EV exhibits genetic heterogeneity: about 40% of patients lack TMC6/8 mutations, and rare autosomal dominant pedigrees implicate other genes such as RHOH, MST1 and CORO1A ((PMID:19706093), (PMID:28646613)). These findings highlight the need for comprehensive genetic testing in EV.
Integrating genetic and functional data, TMC6 is definitively associated with autosomal recessive EV. Diagnostic sequencing of TMC6 informs clinical management, HPV surveillance and skin cancer prevention strategies.
Gene–Disease AssociationDefinitiveBiallelic loss-of-function TMC6 variants in >250 probands across >20 unrelated families with autosomal recessive segregation and concordant functional data Genetic EvidenceStrongAutosomal recessive inheritance of biallelic null TMC6 variants in multiple unrelated families and >50 probands; reached genetic evidence cap Functional EvidenceModerateIn vitro assays show TMC6 interacts with ZnT-1 to regulate zinc homeostasis and forms a complex with TMC8/CIB1 in lymphocytes, consistent with loss-of-function mechanism |