Collection and Analysis of Genetic Polymorphism Relating to Energy Metabolism

能量代谢相关基因多态性的收集与分析

• 批准号: 14572147
• 负责人: MORISAKI Takayuki
• 金额: $ 2.18万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572147/
• 关键词: single nucleotide polymorphism; AMP deaminase; purine nucleotide; genetic mutation; myopathy; ミオパシー; ヌクレオチド代謝

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.

肌腺苷脱氨酶(AMPD)缺乏症是最常见的能量代谢缺陷之一。对于几乎所有患有这种遗传缺陷的人来说，两个连锁突变C34T(Q12X)和C143T的单个突变等位基因是致病的，在普通人群中有很高的等位基因频率。我们感兴趣的是自然选择是否与更高的等位基因频率有关，因为流行病学报告发现C34T等位基因与改善心脏病的临床结果有关。我们分析了230名个体的AMPD1基因座的单核苷酸多态性(SNPs)，其中包括80名德国肌病患者以及来自非洲裔美国人(n=32)、欧洲裔美国人(n=48)、德国人(n=20)和日本人(n=50)的志愿者。为了更好地了解AMPD缺乏症的致病基因，我们对等位基因频率较高的人群进行了研究。根据我们的结果，我们能够定义导致AMPD缺乏症的致病等位基因的祖先单倍型的系统发育树。此外，我们没有发现AMPD缺乏症的杂合子优势。此外，我们在德国肌病患者中发现了两个新的AMPD1错义突变，A860T(K2871)和G930T(M310I)。原核表达研究揭示了这些突变体的功能缺陷。

项目成果

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)

Toyama K、Morisaki H、Kitamura Y、Gross M、Tamura T、Nakahori Y、Vance JM、Speer M、Kamatani N、Morisaki T：“人类 AMPD1 基因的单倍型分析。常见突变等位基因的起源。”J Med Genet。

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)

Kitamura Y 等人：“使用 EM 算法根据基因型数据确定每个受试者的双倍型配置（双倍型分布）的概率分布。”Ann Hum Genet。

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 mitochon

富仓 Y、久美 I、坪井 M、山胁 M、下山 M、山本 Y、佐佐木 N、荻野 K、井川 O、重正 C、石黑 S、大木 S、难波 E、盐田 G、森崎 H、森崎 T、北风 M

Toyama K et al.: "Haplotype Analysis of Human AMPD1 Gene. Origin of Common Mutant Allele."J Med Genet. (In press). (2004)

Toyama K 等人：“人类 AMPD1 基因的单倍型分析。常见突变等位基因的起源。”J Med Genet。

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)

Ito T、Chiku S、Inoue E、Tomita M、Morisaki T、Morisaki H、Kamatani N：“利用合并的 DNA 数据估计每个池中的单倍型频率、连锁不平衡测量和单倍型拷贝的组合。”Am J