HGNC Approved Gene Symbol: DMGDH
SNOMEDCT: 719449007;
Cytogenetic location: 5q14.1 Genomic coordinates (GRCh38): 5:78,997,564-79,069,674 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q14.1 | Dimethylglycine dehydrogenase deficiency | 605850 | Autosomal recessive | 3 |
Dimethylglycine dehydrogenase (DMGDH; EC 1.5.99.2) is an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine (DMG) to form sarcosine. Subsequently, sarcosine dehydrogenase (SDH; 604455; EC 1.5.99.1) converts sarcosine to glycine via a similar reaction. Both enzymes are found as monomers in the mitochondrial matrix, and both contain 1 mol of covalently bound flavin adenine dinucleotide. DMGDH and SDH also utilize a noncovalently bound folate coenzyme that receives the 1-carbon groups that are removed by DMGDH and SDH, forming active formaldehyde.
Binzak et al. (2000) isolated 2 human genomic clones that together contain 16 exons of coding sequence for the DMGDH gene. The DMGDH coding region is 46% identical to that of the gene encoding SDH, while the amino acid sequences are 45% identical. This identity increases to 65% in the region surrounding the flavin attachment site.
By fluorescence in situ hybridization, Binzak et al. (2000) mapped the DMGDH gene to chromosome 5q12.2-q12.3.
Moolenaar et al. (1999) described an inborn error of metabolism of DMGDH characterized by an unusual fish-like body odor (605850). Binzak et al. (2001) detected a homozygous missense mutation (H109R; 605849.0001) in this patient. They also identified several polymorphisms.
In a male patient with DMGDH deficiency (605850) reported by Moolenaar et al. (1999), Binzak et al. (2000) identified a homozygous A-to-G transition at nucleotide 326 of the precursor coding region of the DMGDH cDNA, resulting in a histidine-to-arginine substitution at codon 109 (or residue 81 of the predicted mature protein). The patient, who was of African ancestry, was homozygous for the mutation; there was no information regarding consanguinity of his parents. The patient had a lifelong problem with a fishlike body odor that was first noticed when he was 5 years old. The intensity of the odor increased with physiologic stress, such as illness, as well as during times of increased physical activity. He experienced chronic muscular fatigue beginning in adolescence, accompanied by elevated levels of the muscle form of creatine kinase in serum.
McAndrew et al. (2008) expressed wildtype DMGDH protein and DMGDH with the H109R mutation in E. coli and analyzed enzyme activity. The mutant DMGDH had a 2-fold decrease in flavination, a 65-fold increase in Km, and a 27-fold decrease in activity compared to wildtype protein. McAndrew et al. (2008) concluded that the H109R mutation in DMGDH leads to a significant loss of function, possibly due to abnormal attachment or alignment of bound FAD.
In a Chinese boy with dimethylglycine dehydrogenase deficiency (DMGDHD; 605850), who had persistent elevation of creatine kinase, Wang et al. (2017) identified homozygosity for a c.101+2T-C transition in intron 1 of the DMGDH gene. The mutation was identified by next-generation sequencing and confirmed by Sanger sequencing. Both parents were shown to be carriers.
Binzak, B. A., Vockley, J. G., Jenkins, R. B., Vockley, J. Structure and analysis of the human dimethylglycine dehydrogenase gene. Molec. Genet. Metab. 69: 181-187, 2000. [PubMed: 10767172] [Full Text: https://doi.org/10.1006/mgme.2000.2980]
Binzak, B. A., Wevers, R. A., Moolenaar, S. H., Lee, Y.-M., Hwu, W.-L., Poggi-Bach, J., Engelke, U. F. H., Hoard, H. M., Vockley, J. G., Vockley, J. Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. Am. J. Hum. Genet. 68: 839-847, 2001. [PubMed: 11231903] [Full Text: https://doi.org/10.1086/319520]
McAndrew, R. P., Vockley, J., Kim, J. J. Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R. J. Inherit. Metab. Dis. 31: 761-768, 2008. [PubMed: 18937046] [Full Text: https://doi.org/10.1007/s10545-008-0999-2]
Moolenaar, S. H., Poggi-Bach, J., Engelke, U. F. H., Corstiaensen, J. M. B., Heerschap, A., de Jong, J. G. N., Binzak, B. A., Vockley, J., Wevers, R. A. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin. Chem. 45: 459-464, 1999. [PubMed: 10102904]
Wang, X. L., Yin, F., Zhang, G. Y. DMGDH gene-related dimethylglycine dehydrogenase deficiency in a case. Chinese Pediat. J. 55: 709-710, 2017. Note: Article in Chinese.