Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene.
The molecular genetic defect of a female patient with apolipoprotein A-I (apoA-I) deficiency and premature atherosclerosis was examined. Her parents were first cousins. Her plasma density fraction from 1.063 to 1.21 g/ml contained no apoA-I on SDS/PAGE and no measurable high density lipoprotein cholesterol. Southern blot hybridization showed no gross abnormality to be present in the patient's apoA-I gene and homozygosity for a haplotype of restriction fragment length polymorphisms in the apoA-I gene region. Sequencing after amplification by PCR revealed a codon 84 nonsense mutation (CAG----TAG, Gln----stop) of exon 4 and a codon 67 missense mutation (GCC----ACC, Ala----Thr) of exon 3 in the patient's apoA-I gene. The data from dot-blot hybridization with allele-specific oligonucleotide probes indicated that she was homozygous for the apoA-I gene with regard to the two mutations. The codon 37 missense mutation was also detected in the apoA-I gene of 6 out of 60 controls, who all had normal levels of apoA-I and high density lipoprotein cholesterol, suggesting that the missense mutation is polymorphic and not associated with apoA-I deficiency. These findings indicate that homozygosity for the apoA-I gene with codon 84 nonsense mutation causes the deficiency of apoA-I and of high density lipoprotein cholesterol in the patient.
Matsunaga
T
T
Department of Human Genetics, University of Tsukuba, Japan.
Hiasa
Y
Y
Yanagi
H
H
Maeda
T
T
Hattori
N
N
Yamakawa
K
K
Yamanouchi
Y
Y
Tanaka
I
I
Obara
T
T
Hamaguchi
H
H
D000328:Adult; D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D001161:Arteriosclerosis / Q000000981:diagnostic imaging / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D017023:Coronary Angiography; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005796:Genes; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012016:Reference Values; D015183:Restriction Mapping; D012689:Sequence Homology, Nucleic Acid
D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D003062:Codon; D008075:Lipoproteins, HDL; D015345:Oligonucleotide Probes; D004247:DNA