6533b7d0fe1ef96bd125b825
RESEARCH PRODUCT
Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders
Angelo Balassare CefalùIan Hamilton-craigLuigi CattinSebastiano CalandraA. BellocchioMaurizio AvernaGabriele Bittolo BonLivia PisciottaPaola AlessandriniAlfredo CantaforaDonatella SiepiTommaso FasanoPatrizia TarugiStefano BertoliniElmo Mannarinosubject
AdultMalemedicine.medical_specialtyHeterozygoteSettore MED/09 - Medicina InternaApolipoprotein BAdolescentPremature coronary artery diseaseTangier diseaseCoronary DiseaseBiologyGene mutationmedicine.disease_causeCompound heterozygosityTangier diseaseInternal medicineGenotypeABCA1 genemedicineHumansChildHypoalphalipoproteinemiaSelection BiasAgedApolipoproteins BGeneticsMutationFamilial defective Apo B (FDB)Apolipoprotein A-ICholesterol HDLnutritional and metabolic diseasesMiddle Agedmedicine.diseaseLipoprotein lipaseTangier disease; Familial HDL deficiency; ABCA1 gene; Familial defective Apo B (FDB); Lipoprotein lipase; Premature coronary artery diseaseEndocrinologyChild PreschoolMutationbiology.proteinlipids (amino acids peptides and proteins)Allelic heterogeneityATP-Binding Cassette TransportersFemaleCardiology and Cardiovascular MedicineFamilial HDL deficiencyATP Binding Cassette Transporter 1description
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2004-01-01 |