© 1999 American Heart Association, Inc.
Original Contributions |
Compound Heterozygosity for an Apolipoprotein A1 Gene Promoter Mutation and a Structural Nonsense Mutation With Apolipoprotein A1 Deficiency
From the Departments of Internal Medicine (A.M., J.S., H.H., W.H., M.K., T.K., T.S., K.A.) and Pediatrics (S.I.), Fukuoka University, School of Medicine, 45-1,7-chome Nanakuma, Jonan-ku, Fukuoka 814-80, Japan.
Correspondence to Jun Sasaki, MD, Department of Internal Medicine, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-80, Japan. E-mail mm034515{at}msat.fukuoka-u.ac.jp
Abstract—Apolipoprotein (apo) A1 plays a central role in the metabolism of HDL. We describe a novel genetic variant of the apoA1 gene identified in a patient with low concentrations of plasma HDL cholesterol. The proband, a 12-year-old Japanese boy, exhibited markedly low levels of both plasma apoA1 and HDL cholesterol. Genomic DNA sequencing of apoA1 genes of the patient showed a compound heterozygosity for an A to C substitution at 27 bp upstream of the transcription start site of 1 apoA1 allele, and a C to T substitution in another allele at residue 84 resulting in aberrant termination. The point mutation at nucleotide position –27 changed ATAAATA of the putative TATA box signal sequence to ATACATA. In addition to this mutation, the patient was heterozygous for a G to A substitution at position –75. Immunoblotting of an isoelectric focusing electrophoresis gel of the proband's plasma showed a trace amount of normal apoA1. No measurable plasma apoA1 and HDL cholesterol in a patient with homozygosity for nonsense mutation at residue 84 has been reported previously. To determine the effects of substitution either at position –27 or –75, plasmids containing the 5'-flanking region of the human apoA1 promoter fused to the CAT reporter gene were constructed and transfected in HepG2 cells. A construct with the A to C substitution at position –27 showed 41.8±4.2%, and G to A substitution at position –75 showed 72.8±15.2% (means±SD, n=3) of CAT activities, compared with the wild-type promoter sequence. A construct with the double substitutions at positions –27 and –75 showed only 22.8±1.3% (mean±SD, n=3) activity relative to the wild type. Our patient is the first case with a TATA box mutation etiologically related to lipoprotein disorders.
Key Words: apoA1 • CAT assay • mutation • HDL deficiency • TATA box
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