A case of tangier disease with a novel mutation in the c‐terminal region of ATP‐binding cassette transporter A1

Tangier disease (TD), a rare disorder characterized by extremely low levels of high density lipoprotein cholesterol (HDL‐C), is caused by mutations in the ATP‐binding cassette transporter A1 (ABCA1) gene. Here, we describe a new patient with TD. The 42‐year‐old proband had obvious juvenile cataracts, mild hepatosplenomegaly, and an extremely low level of HDL‐C (1 mg/dl), consistent with the diagnosis of TD. The proband was homozygous for a novel CTC6914‐6TT → 2203X mutation in the carboxy terminus of the ABCA1 protein. ApoAI‐mediated cholesterol efflux from patient fibroblasts was markedly decreased compared to control, despite normal levels of protein expression. This indicates that this mutant protein is normally transcribed and exists as a stable product, yet is functionally defective. These results point to a critical role for the intracellular C‐terminal region of the ABCA1 gene product in regulating cholesterol efflux and HDL‐cholesterol levels. © 2004 Wiley‐Liss, Inc.