Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders

Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unr...

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Bibliographic Details
Published in:Atherosclerosis 2004-02, Vol.172 (2), p.309-320
Main Authors: Pisciotta, Livia, Hamilton-Craig, Ian, Tarugi, Patrizia, Bellocchio, Antonella, Fasano, Tommaso, Alessandrini, Paola, Bon, Gabriele Bittolo, Siepi, Donatella, Mannarino, Elmo, Cattin, Luigi, Averna, Maurizio, Cefalù, Angelo Balassare, Cantafora, Alfredo, Calandra, Sebastiano, Bertolini, Stefano
Format: Article
Language:English
Subjects:
ABCA1 gene
Adolescent
Adult
Aged
Apolipoprotein A-I - blood
Apolipoproteins B - genetics
Atherosclerosis (general aspects, experimental research)
ATP Binding Cassette Transporter 1
ATP-Binding Cassette Transporters - genetics
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Child
Child, Preschool
Cholesterol, HDL - blood
Coronary Disease - genetics
Familial defective Apo B (FDB)
Familial HDL deficiency
Female
Heterozygote
Humans
Lipoprotein lipase
Male
Medical sciences
Middle Aged
Mutation
Premature coronary artery disease
Selection Bias
Tangier disease
Tangier Disease - genetics
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Summary:Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with premature coronary artery disease (pCAD), had a combination of genetic defects. Besides being heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q substitution in apolipoprotein B and the third was a carrier of N291S substitution in lipoprotein lipase. By extending family studies we identified 17 heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these subjects were 38.3 and 36.9% lower than in unaffected family members and similar to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1 mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked and (ii) there may be a selection bias in genotyping towards carriers of ABCA1 mutations who have pCAD possibly related to a combination of genetic and environmental cardiovascular risk factors.
ISSN:0021-9150
1879-1484
DOI:10.1016/j.atherosclerosis.2003.11.009