Mutations in CERS3 Cause Autosomal Recessive Congenital Ichthyosis in Humans

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.

Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia: Clinical Characteristics and Novel and Recurrent Mutations in 132 Patients

“…Lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) are moderately severe forms of ARCI with partially overlapping phenotypes, ranging from coarse to fine scaling and mild to severe erythema (1). Nine genes 1 have so far been implicated in the aetiology of LI and CIE, all encoding epidermal enzymes and transport proteins, such as transglutaminase 1, ichthyin and lipoxygenases E3/12B (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), essential for the formation of a normal stratum corneum (SC) (see e.g. 15,16).…”

Functional study of TGM1 missense mutations in autosomal recessive congenital ichthyosis

“…Background Transglutaminase 1 gene (TGM1), which encodes transglutaminase 1 protein (TGM1), is one of the nine causative genes of autosomal recessive congenital ichthyosis (ARCI) (1). TGMI mutations cause both lamellar ichthyosis (OMIM 242304) (2,3) and congenital ichthyosiform erythroderma (OMIM 242100) (4) of ARCI.…”

Epidermal Barriers

“…These results indicate the essential role of ceramides with very-long-chain acyl moieties in epidermal barrier function. It is not surprising that mutations in CERS3 were recently reported to be responsible for human autosomal recessive congenital ichthyosis (Eckl et al 2013;Radner et al 2013).…”