Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene.

Abstract

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.

Marked reduction of high density lipoprotein cholesterol in mice genetically modified to lack apolipoprotein A-I.

“…In humans an inverse correlation between the risk of developing atherosclerosis and plasma levels of HDL has been observed (12). Human individuals deficient in apoA-I caused by several different types of mutation in the gene appear to be predisposed to atherosclerosis (13)(14)(15)(16)(17)(18). These observations point to the importance of apoA-I and HDL particles in atherogene-SIS.…”

Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I

“…However, in some cases of acquired amyloidosis, full-length wild-type apoA-I has been detected either as the sole component of amyloid fibrils or in association with N-terminal fragments of the protein (23,26). A reverse argument can be formulated by analyzing the case of a patient homozygote for a non-sense mutation at position 84 (50). The absence of amyloid-related organ failure in this case suggests that the presence of an N-terminal truncated form of apoA-I in plasma does not necessarily promote the amyloid sequelae.…”

Apolipoprotein A-I Zavalla (Leu 159 →Pro)

“…1,2,30 Subjects at highest risk include those with apoA-I/C-III/A-IV deficiency, 7,8 reduced apoA-I synthesis, 9 or the presence of additional cardiovascular risk factors. 12,13 There are several mechanisms whereby HDL-C deficiency may enhance CAD risk.…”

“…These cases have ranged from single point mutations in the apoA-I gene to large deletions or chromosomal aberrations in the apoA-I/C-III/ A-IV gene complex. [7][8][9][10] However, HDL-C deficiency states resulting from structural apoA-I changes do not inevitably result in premature CAD. 11 Recently, severe HDL-C deficiency was associated with premature CAD only when accompanied by additional CAD risk factors.…”