Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling

Abstract

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.

Giant solitary trichoepithelioma with desmoplasia on histopathology: An unusual finding

“…Desmoplastic changes have been reported to occur following inflammation [7], other types of tissue injury and neoplasm [6]. Inflammation is commonly associated with the multiple familial variant of trichoepithelioma, particularly the ones caused by CYLD gene mutations [8,9].…”

Formation and removal of poly‐ubiquitin chains in the regulation of tumor necrosis factor‐induced gene activation and cell death

“…All rights reserved Mutations in the CYLD gene are causative for the development of familial cylindromatosis, multiple familial trichoepithelioma and Brooke-Spiegler syndrome, conditions characterized by growth of benign skin tumors occurring mainly in the head and neck areas [90][91][92]. Mice deficient for CYLD are viable and do not spontaneously develop cancer, but are more prone to development of chemically-induced tumors [93] and to colitis-associated inflammation and tumorigenesis [94].…”

Brooke-Spiegler syndrome

“…the folliculo-sebaceous-apocrine germ). They are small skin-colored papules or nodules, with nests of basaloid cells forming cysts containing horn cells (with keratin) (Lee et al, 2005;Kim et al, 2007;Blake and Toro, 2009). …”

“…Spiradenomas may transform into spiradenocarcinomas or show sarcomatous differentiation. An increased risk of developing tumors of the salivary glands has also been described (basalcell adenomas and adenocarcinomas of the parotid glands and minor salivary glands) (Lee et al, 2005;Kim et al, 2007;Blake and Toro, 2009). …”