Recurrent mutations of the apolipoprotein A-I gene in three kindreds with severe HDL deficiency.

Two siblings with high density lipoprotein (HDL) deficiency and no plasma apolipoprotein A-I (Apo A-I) were found to be homozygous for a cytosine deletion in exon 3 of Apo A-I gene (c.85 del C, Q5FsX11). This mutation causes a frameshift leading to a premature stop codon and abolishes the synthesis of Apo A-I. Although both siblings had corneal opacifications and planar xanthomas, only one of them had premature coronary artery disease, probably as the result of mildly elevated LDL levels. In two other unrelated subjects HDL deficiency was due to heterozygosity for a nucleotide substitution in exon 4 of Apo A-I gene (c.494 T>G, L141R). Both Apo A-I mutations were reported previously in an Italian kindred which included compound heterozygotes and simple heterozygotes. We investigated all carriers of these mutations in the three kindreds and in the one previously reported. Plasma Apo A-I and HDL-C levels were lower in the mutation carriers than in non-carrier family members. These levels, however, were lower in L141R carriers than in carriers of c.85 del C. Haplotype analysis performed using several polymorphisms suggested that both the c.85 del C and L141R are likely to be recurrent mutations.