title: Truncation of CGI-58 protein causes malformation of lamellar granules resulting in ichthyosis in Dorfman-Chanarin syndrome.
abstract: Dorfman-Chanarin syndrome is a rare autosomal recessive inherited lipid storage disease characterized by ichthyosis, leukocyte lipid vacuoles, and involvement of several internal organs. Recently, CGI-58 mutations were identified as the cause of Dorfman-Chanarin syndrome. The physiologic roles of the CGI-58 protein and the pathomechanisms of Dorfman-Chanarin syndrome still remain to be clarified, however. The patient, a 16-y-old male, demonstrated ichthyosis, small ears, lipid vacuoles in his leukocytes, liver dysfunction, and mental retardation. Sequencing of CGI-58 revealed that the patient was homozygous for a novel nonsense mutation R184X, in exon 4. The putative truncated protein was 52.4% of the length of the normal CGI-58 polypeptide and lacked approximately 60% of the lipid binding region, 66.4% of the alpha/beta hydrolase folding segment of the polypeptide, and two of the CGI-58 catalytic triads, resulting in a significant loss of lipase/esterase/thioesterase activity. Electron microscopy revealed a large number of abnormal lamellar granules, a disturbed intercellular lamellar structure, and lipid vacuoles in the epidermis. These results suggested that CGI-58 protein is involved in the lipid metabolism of lamellar granules and that defective lipid production in lamellar granules caused by a CGI-58 protein deficiency is involved in the pathogenesis of ichthyosis in Dorfman-Chanarin syndrome.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. akiyama@med.hokudai.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawamura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nomura
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugawara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000293:Adolescent; D004817:Epidermis / Q000648:ultrastructure*; D004950:Esterases / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007057:Ichthyosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008049:Lipase / Q000235:genetics*; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D013577:Syndrome; D011503:Transglutaminases / Q000378:metabolism
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; D011503:Transglutaminases; D004950:Esterases; D008049:Lipase