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: Masashi Akiyama, Daisuke Sawamura, Yuko Nomura, Makoto Sugawara, Hiroshi Shimizu
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 121 Issue 5 Pg. 1029-34 (Nov 2003) ISSN: 0022-202X [Print] United States
• PMID: 14708602 (Publication Type: Journal Article)

Chemical References

• 1-Acylglycerol-3-Phosphate O-Acyltransferase
• ABHD5 protein, human
• Transglutaminases
• Esterases
• Lipase

Topics

• 1-Acylglycerol-3-Phosphate O-Acyltransferase
• Adolescent
• Epidermis (ultrastructure)
• Esterases (genetics)
• Fluorescent Antibody Technique
• Humans
• Ichthyosis (etiology, genetics, pathology)
• Lipase (genetics)
• Lipid Metabolism, Inborn Errors (genetics, pathology)
• Male
• Mutation
• Syndrome
• Transglutaminases (metabolism)