Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency

被引:48
作者
Binzak, BA
Wevers, RA
Moolenaar, SH
Lee, YM
Hwu, WL
Poggi-Bach, J
Engelki, UFH
Hoard, HM
Vockley, JG
Vockley, J
机构
[1] Mayo Clin & Mayo Fdn, Dept Med Genet, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA
[3] Univ Nijmegen Hosp, Inst Neurol, NL-6500 HB Nijmegen, Netherlands
[4] Acad Sinica, Inst Biol Chem, Taipei 115, Taiwan
[5] Natl Taiwan Univ, Coll Med, Inst Biochem Sci, Taipei, Taiwan
[6] Natl Taiwan Univ, Coll Med, Dept Pediat & Med Genet, Taipei, Taiwan
[7] Hop Bicetre AP HP, Lab Biochim 1, Paris, France
[8] SmithKline Beecham, Philadelphia, PA USA
关键词
D O I
10.1086/319520
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Dimethylglycine dehydrogenase (DMGDH) (E.C. number 1.5.99.2) is a mitochondrial matrix enzyme involved in the metabolism of choline, converting dimethylglycine to sarcosine. Sarcosine is then transformed to glycine by sarcosine dehydrogenase (E.C. number 1.5.99.1). Both enzymes use flavin adenine dinucleotide and folate in their reaction mechanisms. We have identified a 38-year-old man who has a lifelong condition of fishlike body odor and chronic muscle fatigue, accompanied by elevated levels of the muscle form of creatine kinase in serum. Biochemical analysis of the patient's serum and urine, using H-1-nuclear magnetic resonance NMR spectroscopy, revealed that his levels of dimethylglycine were much higher than control values. The cDNA and the genomic DNA for human DMGDH (hDMGDH) were then cloned, and a homozygous A-->G substitution (326 A-->G) was identified in both the cDNA and genomic DNA of the patient. This mutation changes a His to an Arg (H109R). Expression analysis of the mutant cDNA indicates that this mutation inactivates the enzyme. We therefore confirm that the patient described here represents the first reported case of a new inborn error of metabolism, DMGDH deficiency.
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页码:839 / 847
页数:9
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