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Haplotype analysis of human AMPD1 gene: origin of common mutant allele
  1. K Toyama1,2,
  2. H Morisaki2,
  3. Y Kitamura3,4,
  4. M Gross5,
  5. T Tamura6,
  6. Y Nakahori6,
  7. J M Vance7,
  8. M Speer7,
  9. N Kamatani3,
  10. T Morisaki1,2
  1. 1Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita 565-8565, Japan
  2. 2Department of Bioscience, National Cardiovascular Center Research Institute, Suita 565-8565, Japan
  3. 3Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan
  4. 4Mitsubishi Research Institute, Tokyo 100-8141, Japan
  5. 5Medizinische Poliklinik-Innenstadt, Universitat Munich, Munich D-80336, Germany
  6. 6Department of Public Health, Tokushima University School of Medicine, Tokushima 770-8503, Japan
  7. 7Center for Human Genetics, Duke University Medical Center, Durham NC 27710, USA
  1. Correspondence to:
 Dr T Morisaki
 Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan;

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Myoadenylate deaminase is a skeletal muscle specific isoenzyme of AMP deaminase (AMPD; EC that plays an important role in regulating adenylate energy charge and nucleotide metabolism. An inherited defect of this enzyme has been reported to be due to a single mutant allele with two linked mutations of C34T (exon 2, Q12X) and C143T (exon 3, P48L) of the AMPD1 gene in almost all cases.1,2 Further, a previous report showed a very high frequency (10−14%) of the C34T allele in whites and African Americans,2 although it has not been found in a Japanese population. Although most individuals with homozygous C34T alleles are assumed to be asymptomatic, some have been reported to show a relatively mild clinical phenotype including exercise induced myalgia.1 Recently, additional findings for missense mutations were reported in Japanese (R388W and R425H)3 and in whites (G468T)4 who showed muscle weakness and myalgia. Therefore, the relationship between abnormal purine nucleotide catabolism and skeletal muscle dysfunction4 is intriguing. In addition, other studies have reported that the C34T allele correlates with improved clinical outcome in patients with heart disease.5,6 We speculated that reduced AMPD activity in skeletal muscle would increase the production of the cardioprotection molecule, adenosine, resulting in increased levels of adenosine in the circulating system, although the fundamental mechanisms responsible for the disorder due to AMPD mutations are unclear.

In the present study, we attempted to determine other AMPD1 mutations and their distribution in ethnically diverse population groups, in order to better understand AMPD1 deficiency and its functional relevance. We identified 35 variations in and around the AMPD1 locus, including newly identified missense mutations. By estimating SNP haplotypes and defining typical haplotypes of the AMPD1 locus, we were also able to describe a phylogenic tree for ancestral AMPD1 haplotypes …

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