Cloning of Dimethylglycine Dehydrogenase and a New Human Inborn Error of Metabolism, Dimethylglycine Dehydrogenase Deficiency

Abstract

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 (1)H-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.

Bioinformatic Analyses of Renal Ischaemia-Reperfusion Injury Models: Identification of Key Genes Involved in the Development of Kidney Disease

“…Dimethylglycine dehydrogenase, encoded by Dmgdh, is a mitochondrial matrix enzyme involved in the metabolism of choline to glycine [34]. Glycine was reported to possess anti-inflammatory and immunomodulatory roles against ischaemia-induced renal injury [35].…”

Proteomic analysis of silver nanoparticle toxicity in rat

“…This enzyme participates in glycine, serine, and threonine metabolism with FAD as a cofactor 72,73 . Reduced DMGDH expression has been reported as an inborn error of metabolism and is characterized by a fishlike body odor, chronic muscle fatigue, and elevated levels of the muscle form of creatine kinase found in serum 74,75 . It has not yet been reported to be related to SNP toxicity, but reduced DMGDH expression seems to be related to a mitochondrial defect caused by SNP deposition, and the subsequent reduction of glycine, serine, and threonine catabolic processes might aid in the apoptotic response in SNP exposed tissues.…”

Clinical utility gene card for: Trimethylaminuria

“…Note: on the basis of smell, trimethylaminuria can be difficult to distinguish from other conditions that give rise to an unpleasant body odour, including poor hygiene, forms of gingivitis and blood-borne halitosis, 29 or the rare inherited metabolic disorder dimethylglycinuria, caused by a deficiency of dimethylglycine dehydrogenase. 30 Biochemistry: diagnosis is based on the percent of total trimethylamine (free trimethylamine plus the non-odorous trimethylamine N-oxide) excreted in the urine as the unmetabolized free amine. 6,24,31 440%: severe trimethylaminuria.…”