Abstract 620: Identification of Novel ABCA1 Mutations in Families With Tangier Disease

Abstract

Tangier disease is an extremely rare, autosomal recessive disorder caused by mutations in the ABCA1 gene, and is characterized by near absence of plasma high density lipoprotein cholesterol, cholesterol accumulation in multiple tissues, peripheral neuropathy and accelerated atherosclerosis. Here we report three kindreds with Tangier disease. We describe two novel coding mutations in the ABCA1 gene that result in premature truncation of the protein as well as a novel intronic variant that leads to creation of a cryptic splice site acceptor resulting in aberrant mRNA splicing and premature truncation of the protein. We also show that this mutation arose de novo in the proband, the first demonstration of a pathogenic de novo mutation in ABCA1 associated with Tangier disease. Our findings expand the list of pathogenic mutations in ABCA1 and our understanding of how mutations in this gene lead to abnormal cellular and physiological phenotypes.