Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations

Background. High density lipoproteins (HDL) are complex lipoprotein particl es involved in reverse cholesterol (C) transport and are negatively associa ted with the risk for coronary artery disease (CAD). We have described a di sorder of familial HDL deficiency (FHD) due to abnormal cellular cholestero l efflux. In the present study, we investigated cellular cholesterol efflux on skin fibroblast from 15 probands with moderate to severe hypoalphalipop roteinemia, including one subject with Tangier disease (TD). We performed f amily studies on eight of these probands (269 individuals) with familial hy poalphalipoproteinemia (defined as a HDL-C < 5th%, and with no known cause of HDL deficiency). We have previously shown that four of our FHD patients and patients with TD have mutations at the ABC1 gene, demonstrating that FH D is a heterozygous form of TD. Methods. On each subject, we carried out de tailed biochemical analysis and determined apoA-I-mediated cellular cholest erol efflux using H-3-cholesterol labeled skin fibroblasts from study subje cts compared with controls. TD has also been associated with abnormal cellu lar cholesterol efflux. Cell fusion experiments with polyethylene glycol (P EG) were carried out with fibroblasts from a subject with TD and one with F HD in order to determine whether the Tangier cells can complement the FHD d efect. In all subjects with a reduced cellular cholesterol efflux, exons of the ABCA1 gene were sequenced. Results. Familial forms of HDL deficiency, defined as HDL-C levels < 5th percentile, are a heterogeneous group of lipo protein disorders. A reduced cellular cholesterol efflux has been identifie d in eight subjects from seven kindred (7/14 or 50% of probands tested), be ing reduced by a mean 59% of controls (range 49-63%).In four of these subje cts, a mutation at the ABCA1 gene locus was identified. In three other subj ects an efflux defect was identified but no critical mutation at the ABCA1 gene locus has been identified. In the remaining subjects, (7/14), no efflu x defect was identified. Complementation studies reveal that the FHD defect is not corrected by Tangier cells, confirming that FHD and TD represent a spectrum of the same genetic defect. Conclusion. Familial hypoalphalipropot einemia syndromes are phenotypically heterogeneous; one form is associated with abnormal cellular cholesterol efflux caused by heterozygous mutations at the ABCA1 gene, that defines familial HDL Deficiency while homozygous mu tations or compound heterozygocity causes TD. Other forms are primary hypoa lphalipoproteinemia of unknown cause, while the remaining cases are associa ted with hypertriglyceridemia with or without elevated apoB levels. We conc lude that a cellular cholesterol defect is a relatively frequent cause of f amilial HDL deficiency and that. a mutation at the ABCA1 gene can be identi fied in half of these patients. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.