Collection and Analysis of Genetic Polymorphism Relating to Energy Metabolism

肌腺苷酸脱氨酶（AMPD）缺乏是能量代谢中最常见的缺陷之一。对于几乎所有具有这种遗传缺陷的个体，两个连锁突变C34T（Q12X）和C143T的单个突变等位基因是致病的，在一般人群中具有高等位基因频率。我们感兴趣的是，自然选择是否可能参与更高的等位基因频率，流行病学报告发现C34T等位基因与改善心脏病的临床结果。我们分析了230名个体AMPD 1基因座的单核苷酸多态性（SNP），其中包括80名德国肌病患者以及来自非裔美国人（n=32），欧洲裔美国人（n=48），德国人（n=20）和日本人（n=50）种族的志愿者。为了更好地了解AMPD缺乏症的致病等位基因，我们研究了等位基因频率较高的人群。从我们的结果，我们能够定义一个祖先的单倍型负责AMPD缺乏症的致病等位基因的基因树。此外，我们没有发现AMPD缺陷的杂合子优势。此外，我们在德国肌病患者中发现了2个新的AMPD 1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。

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.