Collection and Analysis of Genetic Polymorphism Relating to Energy Metabolism

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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.