Structure and analysis of the human dimethylglycine dehydrogenase gene

Dimethylglycine dehydrogenase (DMGDH; E.C. 1.5.99.2) is an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dim ethylglycine (DMG) to form sarcosine, Subsequently, sarcosine dehydrogenase (SDH; E.C, 1.5.99.1) converts sarcosine to glycine via a similar reaction, Both enzymes are found as monomers in the mitochondrial matrix, and both c ontain 1 mol of covalently bound flavin adenine dinucleotide. DMGDH and SDH also utilize a noncovalently bound folate coenzyme that receives the "1-ca rbon" groups that are removed by DMGDH and SDH, forming "active formaldehyd e." We have recently described a new inborn error of metabolism of DMGDH ch aracterized by an unusual fish-like body odor, To augment our study of this new disorder, we have isolated two human genomic clones that together cont ain 16 exons of coding sequence for the hDMGDH gene. Fluorescent in situ hy bridization analysis of the hDMGDH gene indicates that it is found on chrom osome 5q12.2-q12.3. In addition, several polymorphisms have been identified in the hDMGDH cDNA sequence, Population analysis of two Ser/Pro polymorphi sms found 367 amino acids apart reveals a skew of alleles, with the haploty pes Ser/Pro or Pro/Ser (79%) overrepresented compared to the number of Ser/ Ser or Pro/Pro alleles observed, Possible functional consequences of these findings are discussed, Characterization of the gene structure for hDMGDH w ill aid in the study of patients with inherited defects of this enzyme, (C) 2000 Academic Press.