title: 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.
authors.affiliation: Institute for Human Genetics, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Franz P W
authors.initials: FP
authors.lastname: Radner
authors.forename: Slaheddine
authors.initials: S
authors.lastname: Marrakchi
authors.forename: Peter
authors.initials: P
authors.lastname: Kirchmeier
authors.forename: Gwang-Jin
authors.initials: GJ
authors.lastname: Kim
authors.forename: Florence
authors.initials: F
authors.lastname: Ribierre
authors.forename: Bourane
authors.initials: B
authors.lastname: Kamoun
authors.forename: Leila
authors.initials: L
authors.lastname: Abid
authors.forename: Michael
authors.initials: M
authors.lastname: Leipoldt
authors.forename: Hamida
authors.initials: H
authors.lastname: Turki
authors.forename: Werner
authors.initials: W
authors.lastname: Schempp
authors.forename: Roland
authors.initials: R
authors.lastname: Heilig
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000818:Animals; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics*; D009154:Mutation; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D014416:Tunisia
chemical_list: D022821:RNA Splice Sites; D062085:RNA, Long Noncoding; D013107:Sphingolipids; C583317:CERS3 protein, human; D051049:Sphingosine N-Acyltransferase; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C579149:ADAMTS17 protein, human