title: Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.forename: Ian
authors.initials: I
authors.lastname: Hamilton-Craig
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
authors.forename: Antonella
authors.initials: A
authors.lastname: Bellocchio
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fasano
authors.forename: Paola
authors.initials: P
authors.lastname: Alessandrini
authors.forename: Gabriele Bittolo
authors.initials: GB
authors.lastname: Bon
authors.forename: Donatella
authors.initials: D
authors.lastname: Siepi
authors.forename: Elmo
authors.initials: E
authors.lastname: Mannarino
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Averna
authors.forename: Angelo Balassare
authors.initials: AB
authors.lastname: Cefalù
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cantafora
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood; D001055:Apolipoproteins B / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D008076:Cholesterol, HDL / Q000097:blood; D003327:Coronary Disease / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015983:Selection Bias; D013631:Tangier Disease / Q000235:genetics*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL