Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux

• Published in: The Lancet (British edition) Vol. 354; no. 9187; pp. 1341 - 1346
• Main Authors: MARCIL, M, BROOKS-WILSON, A, OUELLETTE, B. F. F, SENSEN, C. W, FICHTER, K, MOTT, S, DENIS, M, BOUCHER, B, PIMSTONE, S, GENEST, J. JR, KASTELEIN, J. J. P, HAYDEN, M. R, CLEE, S. M, ROOMP, K, ZHANG, L.-H, LU YU, COLLINS, J. A, VAN DAM, M, MOLHUIZEN, H. O. F, LOUBSTER, O
• Format: Journal Article
• Language: English
• Published: London Lancet 16.10.1999; Elsevier Limited
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Cholesterol; Cholesterol - metabolism; Cholesterol, HDL - deficiency; Errors of metabolism; Exons; Female; Genetics; Genotype; Glycoproteins - genetics; Humans; Hypolipoproteinemias - genetics; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical sciences; Metabolic diseases; Middle Aged; Mutation; Pedigree; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Proteins; Tangier Disease - genetics; Hypolipemia; Human; Hypoalphalipoproteinemia; Deficiency; Metabolic diseases; Genotype; Lipids; Genetic disease; Gene; Cholesterol HDL; Etiology; Mutation; Dyslipemia; Molecular biology
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(99)07026-9

A low concentration of HDL cholesterol is the most common lipoprotein abnormality in patients with premature atherosclerosis. We have shown that Tangier disease, a rare and severe form of HDL deficiency characterised by a biochemical defect in cellular cholesterol efflux, is caused by mutations in the ATP-binding-cassette (ABC1) gene. This gene codes for the cholesterol-efflux regulatory protein (CERP). We investigated the presence of mutations in this gene in patients with familial HDL deficiency. Three French-Canadian families and one Dutch family with familial HDL deficiency were studied. Fibroblasts from the proband of each family were defective in cellular cholesterol efflux. Genomic DNA of each proband was used for mutation detection with primers flanking each exon of the ABC1 gene, and for sequencing of the entire coding region of the gene. PCR and restriction-fragment length polymorphism assays specific to each mutation were used to investigate segregation of the mutation in each family, and to test for absence of the mutation in DNA from normal controls. A different mutation was detected in ABC1 in each family studied. Each mutation either created a stop codon predicted to result in truncation of CERP, or altered a conserved aminoacid residue. Each mutation segregated with low concentrations of HDL-cholesterol in the family, and was not observed in more than 500 control chromosomes tested. These data show that mutations in ABC1 are the major cause of familial HDL deficiency associated with defective cholesterol efflux, and that CERP has an essential role in the formation of HDL. Our findings highlight the potential of modulation of ABC1 as a new route for increasing HDL concentrations.