TMC8 – Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent plane warts and pityriasis versicolor–like lesions with high risk of cutaneous carcinoma. EV follows mainly an autosomal recessive inheritance and is caused by biallelic loss-of-function variants in TMC6 (EVER1) or TMC8 (EVER2) (PMID:12426567).

Initial mapping of the EV1 locus to chromosome 17q25 and subsequent identification of nonsense and splice site mutations in TMC8 provided strong genetic evidence for EVER2 deficiency in multiple unrelated families (PMID:12426567). A Chinese consanguineous pedigree demonstrated a homozygous c.568C>T (p.Arg190Ter) variant leading to premature truncation and absence of 537 amino acids in EVER2 (PMID:16045695).

Subsequent case series and familial studies have reported homozygous and compound heterozygous TMC8 variants (nonsense, frameshift, splice) in at least 10 unrelated probands with clear autosomal recessive segregation and recurrent c.568C>T (p.Arg190Ter) in East Asian patients (PMID:12426567; PMID:16045695). The variant spectrum includes missense, splice donor/acceptor, frameshift and deep-intronic changes.

Functional assays revealed that EVER2 forms a complex with ZnT-1 to regulate intracellular zinc distribution and down-regulates zinc-stimulated transcription factors in keratinocytes. Loss of EVER2 increases zinc influx to nucleoli, enhances keratinocyte proliferation, and mirrors the EV phenotype (PMID:18158319).

Further mechanistic studies showed that TMC8 interacts with CIB1 in lymphocytes to stabilize a heterotrimeric complex required for antiviral immunity, and EVER2-deficient T cells exhibit mild memory skewing, supporting a cell-intrinsic immune defect in EV (PMID:32917726).

Taken together, biallelic TMC8 variants cause autosomal recessive EV with definitive clinical validity. Familiar and population screening for recurrent LoF variants enables early diagnosis, genetic counseling, and surveillance for cutaneous carcinomas.

References

• Nature Genetics • 2002 • Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. PMID:12426567
• Clinical and Experimental Dermatology • 2005 • A homozygous nonsense mutation in the EVER2 gene leads to epidermodysplasia verruciformis. PMID:16045695
• The Journal of Experimental Medicine • 2008 • Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. PMID:18158319
• Journal of the European Academy of Dermatology and Venereology : JEADV • 2017 • Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease. PMID:28646613

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