Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the US. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African-Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; twenty (17%) nonsense; nine (8%) deletion; eight (7%) splice-site and seven (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34 % (147/435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36/115) of all mutations and 41% (29/71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35/71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C> T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum, summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5′ methylated CpG dinucleotides. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations.
Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 CYLD mutations have been reported, occurring in exons 9–20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma. CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the NF-kappaB and c-Jun N-terminal kinase pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked ubiquitin (Ub) chains but has been shown to act on K48-linked Ub chains as well. In 2008 the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD’s unique specificity for K63-linked ubiquitin chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, anti-microbial defense and inflammation.
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