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

Abstract

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.

PPARγ1 and LXRα face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1

“…The importance of ABCA1 function as a cholesterol efflux mediator is illustrated by Tangier disease, a genetic disorder characterized by extremely low plasma HDL levels and remarkable accumulation of cholesterol in macrophages localized in the tonsils, spleen, liver, and intestine [Serfaty-Lacrosniere et al, 1994]. Numerous studies have demonstrated that familial Tangier disease mainly results from mutations in the ABCA1 gene [Altilia et al, 2003; Bodzioch et al, 1999; Brooks-Wilson et al, 1999; Guan et al, 2004; Hooper et al, 2009; Maekawa et al, 2009; Rust et al, 1998; Singaraja et al, 2006]. Moreover, macrophages isolated from Tangier patients express significantly lower levels of ABCG1 [Lorkowski et al, 2001].…”

“…The importance of ABCA1 function as a cholesterol efflux mediator is illustrated by Tangier disease, a genetic disorder characterized by extremely low plasma HDL levels and remarkable accumulation of cholesterol in macrophages localized in the tonsils, spleen, liver, and intestine [Serfaty-Lacrosniere et al, 1994]. Numerous studies have demonstrated that familial Tangier disease mainly results from mutations in the ABCA1 gene [Altilia et al, 2003;Bodzioch et al, 1999;Brooks-Wilson et al, 1999;Guan et al, 2004;Hooper et Upon uptake of oxLDL by macrophages, oxysterols are synthesized, which allows activation of PPARγ1 and LXRα. Once activated, PPARγ1 and LXRα not only induce the expression of each other, but they also induce the expression of many ABC transporters, as well as that of ApoE.…”

Reduced cellular cholesterol efflux and low plasma high-density lipoprotein cholesterol in a patient with type B Niemann-Pick disease because of a novel SMPD-1 mutation

“…12 Primary cultures were grown in Dulbecco's modified Eagle's medium (DMEM; Gibco, Grand Island, NY) supplemented with 10% fetal calf serum (FCS; Gibco). The cells were used for the measurements of ASM activity, the cellular lipid efflux, and mRNA expression.…”