title: Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome.
abstract: Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A.
authors.affiliation: Department of Dermatology, Columbia University, Russ Berrie Medical Science Pavilion, New York, NY 10032, USA.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cabral
authors.forename: Mazen
authors.initials: M
authors.lastname: Kurban
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wajid
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
authors.forename: Lynn
authors.initials: L
authors.lastname: Petukhova
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western / Q000379:methods; D002874:Chromosome Mapping; D003241:Consanguinity; D003873:Dermatitis, Exfoliative / Q000235:genetics* / Q000503:physiopathology; D004817:Epidermis / Q000473:pathology; D059472:Exome; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D008040:Genetic Linkage; D006025:Glycosaminoglycans / Q000032:analysis; D006720:Homozygote; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010859:Pigmentation Disorders / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D012871:Skin Diseases / Q000151:congenital; D015238:Sulfotransferases / Q000235:genetics*
chemical_list: D006025:Glycosaminoglycans; C013786:A73025; C092527:N-acetylgalactosamine-4-sulfotransferase; D015238:Sulfotransferases