Collection and Analysis of Genetic Polymorphism Relating to Energy Metabolism

2003 Fiscal Year Final Research Report Summary

• Project/Area Number: 14572147
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: MORISAKI Takayuki National Cardiovascular Center Research Institute, Department of Bioscience, Director, バイオサイエンス部, 部長 (30174410)
• Co-Investigator(Kenkyū-buntansha): HIDAKA Kyoko National Cardiovascular Center Research Institute, Department of Bioscience, Laboratory Chief, バイオサイエンス部, 室長 (00216681) ; MORISAKI Hiroko National Cardiovascular Center Research Institute, Department of Bioscience, Laboratory Chief, バイオサイエンス部, 室長 (40311451)
• Project Period (FY): 2002 – 2003
• Keywords: single nucleotide polymorphism / AMP deaminase / purine nucleotide / genetic mutation / myopathy / ミオパシー

Research Abstract

Myoadenylate deaminase (AMPD) deficiency is one of the most common defect in energy metabolism. For nearly all individuals with this inherited deficiency, a single mutant allele of two linked mutations, C34T (Q12X) and C143T, is causative, with a high allele frequency in the general population. We are interested in whether natural selection might be involved in higher allele frequency, as epidemiological reports have found the C34T allele to be associated with improved clinical outcome in heart disease. We analyzed single-nucleotide polymorphisms (SNPs) in the AMPD1 locus in 230 individuals, which included 80 German myopathic patients as well as volunteers from African American (n=32), European American (n=48), German (n=20), and Japanese (n=50) ethnic groups. To better understand the causative allele of AMPD deficiency, we population groups with a high allele frequency. From our results, we were able to define a phylogenic tree of ancestral haplotypes responsible for the causative allele of AMPD deficiency. Also, we did not find heterozygote advantage for AMPD deficiency. Further, we identified 2 new missense mutations for AMPD1, A860T (K2871) and G930T (M310I), in the German myopathic patients. A prokaryotic expression study revealed a functional defect for these mutants.

Research Products

• [Publications] Kitamura Y et al.: "Determination of probability distribution of diplotype configuration (diplotype distribution) for each subject from genotypic data using the EM algorithm."Ann Hum Genet. 66. 183-193 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ito T et al.: "Estimation of haplotype frequencies, linkage-disequilibrium measures, and combination of haplotype copies in each pool by use of pooled DNA data."Am J Hum Genet. 72. 384-398 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tomikura Y et al.: "Coordinate induction of AMP deaminase in human atrium with mitochondrial DNA deletion."Biochem Biophys Res Commun. 302. 372-376 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Toyama K et al.: "Haplotype Analysis of Human AMPD1 Gene. Origin of Common Mutant Allele."J Med Genet. (In press). (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kitamura Y, Moriguchi M, Kaneko H, Morisaki H, Morisaki T, Toyama K, Kamatani N: "Determination of probability distribution of diplotype configuration (diplotype distribution) for each subject from genotypic data using the EM algorithm."Ann Hum Genet. 66. 183-193 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ito T, Chiku S, Inoue E, Tomita M, Morisaki T, Morisaki H, Kamatani N: "Estimation of haplotype frequencies, linkage-disequilibrium measures, and combination of haplotype copies in each pool by use of pooled DNA data."Am J Hum Genet. 72. 834-398 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tomikura Y, Hisatome I, Tsuboi M, Yamawaki M, Shimoyama M, Yamamoto Y, Sasaki N, Ogino K, Igawa O, Shigemasa C, Ishiguro S, Ohgi S, Nanba E, Shiota G, Morisaki H, Morisaki T, Kitakaze M: "Coordinate induction of AMP deaminase in human atrium with mitochondrial DNA deletion."Biochem Biophys Res Commun. 302. 372-376 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Toyama K, Morisaki H, Kitamura Y, Gross M, Tamura T, Nakahori Y, Vance JM, Speer M, Kamatani N, Morisaki T: "Haplotype Analysis of Human AMPD1 Gene. Origin of Common Mutant Allele."J Med Genet. (in press). (2004)
  • Description: 「研究成果報告書概要(欧文)」より