We investigated the molecular defect causing
high density lipoprotein cholesterol (HDL-C) deficiency in a male proband and his family members. Amplification and sequencing of genomic
DNA disclosed a novel base-pair substitution at residue 159 in the
apolipoprotein (
apo) A-I gene. This substitution resulted in the loss of an AviII restriction site and a predicted substitution of
leucine with
proline at residue 159. Restriction
enzyme analysis demonstrated absence of the AviII site in 19 of 40
biological family members. Compared with familial controls, subjects with the
apoA-I(Zavalla) variant had reduced HDL-C (1.16 versus 0.27 mmol/L, P<0.0001),
apoA-I (38.7 versus 124.4 mg/dL, P<0.0001), and
apoA-II (14.3 versus 19.0 mg/dL, P<0.0001) levels. Two subjects who have developed
coronary artery disease to date possess additional cardiovascular risk factors. Other heterozygotes for
apoA-I(Zavalla) are presently without symptomatic
coronary artery disease. This study identifies a monogenic cause of
hypoalphalipoproteinemia, with the single base-pair substitution having a dominant effect on the low HDL-C phenotype. In addition, it extends recent observations that HDL-C deficiency states may be more prone to the development of premature
coronary artery disease when accompanied by additional cardiovascular risk factors.