1992 Fiscal Year Final Research Report Summary
Autosomal dominant hypercholesterolemia due to mutant apolipoprotein B genes
| Project/Area Number |
03671090
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Human genetics
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| Research Institution | Basic Medical Sciences, University of Tsukuba |
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Principal Investigator |
HAMAGUCHI Hideo Univ.Tsukuba Med.Genet. Professor, 基礎医学系, 教授 (00091918)
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| Co-Investigator(Kenkyū-buntansha) |
ARINAMI Tadao Univ.Tsukuba Med.Genet. Assistant professor, 基礎医学系, 講師 (10212648)
KOBAYASHI Kimiko Univ.Tsukuba Med.Genet. Assistant professor, 基礎医学系, 講師 (90215319)
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| Project Period (FY) |
1991 – 1992
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| Keywords | Hypercholesterolemia / Apolipoprotein B gene / LDL receptor gene / Coronary heart disease / Familial hypercholesterolemia / 常染色体性優性遺伝 |
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| Research Abstract |
Autosomal dominant hypercholesterolemia is an important risk factor for premature coronary heart disease. This study was done to clarify whether autosomal dominant hypercholesterolemia due to mutant apolipoprotein B genes is relatively common. The genes for LDL receptor and apolipoprotein B were analyzed in 45 pedigrees with hypercholesterolemia. Five different partial deletions, two different frameshift mutations and one complex nucleotide sequence changes were detected in the LDL receptor genes from 11 pedigrees. Seven of the 8 mutant LDL receptor mutant genes were novel ones. In addition, LDL receptor gene RFLP haplotype analysis did not deny the possibility that hypercholesterolemia of another 19 pedigrees is due to mutant LDL receptor genes. Hypercholesterolemia was relatively severe(serum cholesterol levels>300mg/dl)and Achilles tendon xanthomas were frequently observed in most of the above 30 pedigrees. In the other 15 pedigrees, hypercholesterolemia and LDL receptor gene RFLP h
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aplotypes were not co-segregated, suggesting that hypercholesterolemia is due to a mutation of the gene(s) other than the LDL receptor gene. Hypercholesterolemia was moderate (serum cholesterol levels, 250-300mg/dl) and Achilles tendon xanthomas were seldom observed in these 15 pedigrees. A linkage analysis between hypercholesterolemia and the genetic markers within the apolipoprotein B gene was done in the 15 pedigrees. In three of the 15 pedigrees, hypercholesterolemia and the genetic marker was not co-segregated. As to the other 12 pedigrees, the linkage analysis was not infomative. For these 12 pedigrees, DNA sequences in the region of the apolipoprotein B gene that codes for the LDL receptor-binding domain have been analyzed in the probands. Thus far, however, abnormalities in the DNA sequences of the apolipoprotein B gene have not been detected. These data suggest that many of hereditary moderate hypercholesterolemia are not due to the mutant LDL receptor genes, though most of relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas are caused by the mutant LDL receptor genes. Further studies are needed to reveal the prevalence of autosomal dominant hypercholesterolemia due to the mutant apolipoprotein B genes. Less
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