Alternative titles; symbols
HGNC Approved Gene Symbol: MDH1
Cytogenetic location: 2p15 Genomic coordinates (GRCh38): 2:63,588,963-63,607,197 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p15 | ?Developmental and epileptic encephalopathy 88 | 618959 | Autosomal recessive | 3 |
Malate dehydrogenase (EC 1.1.1.37) catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. Two isozymes are known, one in the cytosol (MDH1) and the other in the mitochondria (MDH2; 154100) (summary by Tanaka et al., 1996).
Cytosolic MDH is identical to the enzyme previously described as aromatic alpha-keto acid reductase (KAR). The reduction of aromatic alpha-keto acids is a secondary function of MDH1 (Friedrich et al., 1987; Friedrich et al., 1988).
Friedrich et al. (1987, 1988) presented evidence from several nonhuman species and from humans that alpha-ketoacid reductase and cytoplasmic malate dehydrogenase are identical. In starch-gel electrophoresis the 2 enzyme functions comigrated in all species studied except some marine species. Inhibition with malate, the end-product of the MDH reaction, substantially reduced or totally eliminated KAR activity. Genetically determined electrophoretic variants of MDH1 seen in fresh water bony fish and in the amphibian Rana pipiens exhibited identical variation of KAR, and the 2 traits cosegregated in the offspring from 1 R. pipiens heterozygote studied. Both enzymes comigrated with no electrophoretic variation among several inbred strains of mice. Antisera raised against purified chicken MDH1 totally inhibited both MDH1 and KAR activity in chicken liver homogenates. In all species examined, KAR activity was associated only with cytoplasmic MDH, not with mitochondrial MDH.
Tanaka et al. (1996) isolated a human cDNA encoding a protein of 334 amino acids that showed 96% identity in amino acid sequence to murine cytosolic malate dehydrogenase. Among the adult human tissues examined by Northern blot analysis, heart and skeletal muscle expressed this gene most highly.
Chu et al. (1975) presented cell-hybrid evidence for synteny of gal-1-PT, acid phosphatase, MDH1 and gal-plus-activator and for assignment to chromosome 2.
By fluorescence in situ hybridization, Tanaka et al. (1996) mapped the MDH1 gene to chromosome 2p16. This localization was somewhat different from that earlier determined by less precise methods, i.e., analysis of enzyme activity in somatic cell hybrids and deletion mapping.
In the mouse, the cytosolic form of malate dehydrogenase is determined by a gene symbolized Mor2 and the mitochondrial form by a gene symbolized Mor1 (the opposite numbering system from that used with the mitochondrial and cytosolic isozymes in the human). Ball et al. (1994) induced a mutant Mor2 allele and used it to map the gene to mouse chromosome 11 in a region of homology with human chromosome 2 by linkage analysis.
Zhao et al. (2010) showed that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism in the human liver. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated enoyl-coenzyme A hydratase/3-hydroxyacyl-coenzyme A dehydrogenase (607037) in fatty acid oxidation and malate dehydrogenase in the TCA cycle, inhibited argininosuccinate lyase (608310) in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase (261680) in gluconeogenesis. Zhao et al. (2010) concluded that acetylation plays a major role in metabolic regulation.
In HEK293 cells that were deficient in MDH1 and in dried blood spots from 2 patients with early infantile epileptic encephalopathy-88 (618959), Broeks et al. (2019) found increased levels of glycerol-3-phosphate. The authors suggested that this finding might represent a compensatory mechanism to enhance oxidation of NADH in the cytosol by the glycerol-3-phosphate shuttle.
Mitochondrial and soluble MDHs agree with the rule that the 2 forms of enzymes are coded by different chromosomes. However, Birktoft et al. (1982) found close structural homology of the 2 (as well as lactate dehydrogenase, see 150000) and concluded that they were derived from a common ancestral gene.
Davidson and Cortner (1967) observed an inherited variant of supernatant malate dehydrogenase of erythrocytes. The variant was found in a black woman and her 2 sons during a survey of 1470 blacks and 1440 whites. The electrophoretic nature of the variant suggested that the molecule is a dimer with mutation in the gene controlling one of the elements and that this gene is autosomal.
Developmental and Epileptic Encephalopathy 88
In 2 first cousins from a consanguineous Saudi family with developmental and epileptic encephalopathy-88 (DEE88; 618959), Broeks et al. (2019) identified a homozygous mutation in the MDH1 gene (A138V; 154200.0001). The mutation, which was identified by autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. MDH1 protein levels were reduced in lymphoblastoid cells and fibroblasts from the patients.
Shows (1972) presented cell hybridization data suggesting that soluble malate dehydrogenase and isocitrate dehydrogenase (IDH; 147700) are syntenic.
Larson et al. (1982) mapped MDH1 to 2p23 by gene dosage.
By study of human-Chinese hamster somatic cell hybrids, Donald (1982) concluded that the gene for KAR is on chromosome 12. Interestingly, the substrate specificity of KAR overlaps that of lactate dehydrogenase which, in one of its isozymic forms, is also determined by a gene on chromosome 12 (LDH; see 150100). However, the enzymes are distinctly different in electrophoretic mobility and subunit composition.
Friedrich et al. (1988) called into question the assignment of KAR to chromosome 12 in somatic cell hybrids because interspecific hybrid bands of both MDH1 and LDH appeared with slightly different mobility approximately midway between the human and hamster controls in somatic cell hybrid studies. Friedrich et al. (1988) concluded that the bulk of KAR activity in human blood is due to MDH1, with a minor fraction catalyzed by lactate dehydrogenase, as is the case in most other species studied.
In a single person, Donald (1982) found an unusual phenotype of KAR following electrophoresis in starch gel and interpreted this to represent a genetic variant.
Friedrich and Ferrell (1985) found no variants in a starch gel electrophoresis of 509 persons from many different racial groups and none in a survey by thin-layer isoelectric focusing in polyacrylamide gel involving 232 persons.
In 2 first cousins, aged 2.5 and 4 years, from a consanguineous Saudi family with developmental and epileptic encephalopathy-88 (DEE88; 618959), Broeks et al. (2019) identified homozygosity for a c.413C-T transition (c.413C-T, NM_001199111) in the MDH1 gene, resulting in an ala138-to-val (A138V) substitution at a highly conserved residue in the NAD(+)-binding domain. The mutation, which was found by autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The variant was not found in the gnomAD database or in a local database of approximately 2,300 ethnically matched exomes. MDH1 protein levels were reduced in lymphoblastoid cells and fibroblasts from both patients compared to controls. The patients had onset of seizures in the first months of life.
Ball, S. T., Moseley, H. J., Peters, J. Mor2, supernatant malate dehydrogenase, is linked to wa2 and Hba on mouse chromosome 11 in a region of homology with human chromosome 2p. Genomics 24: 399-400, 1994. [PubMed: 7698769] [Full Text: https://doi.org/10.1006/geno.1994.1637]
Birktoft, J. J., Fernley, R. T., Bradshaw, R. A., Banaszak, L. J. Amino acid sequence homology among the 2-hydroxy acid dehydrogenases: mitochondrial and cytoplasmic malate dehydrogenases form a homologous system with lactate dehydrogenase. Proc. Nat. Acad. Sci. 79: 6166-6170, 1982. [PubMed: 6959107] [Full Text: https://doi.org/10.1073/pnas.79.20.6166]
Blake, N. M., Kirk, R. L., Simons, M. J., Alpers, M. P. Genetic variants of soluble malate dehydrogenase in New Guinea populations. Humangenetik 11: 72-74, 1970. [PubMed: 5490358] [Full Text: https://doi.org/10.1007/BF00296307]
Broeks, M. H., Shamseldin, H. E., Alhashem, A., Hashem, M., Abdulwahab, F., Alshedi, T., Alobaid, I., Zwatkruis, F., Westland, D., Fuchs, S., Verhoeven-Duif, N. D., Jans, J. J. M., Alkuraya, F. S. MDH1 deficiency is a metabolic disorder of the malate-aspartate shuttle associated with early onset severe encephalopathy. Hum. Genet. 138: 1247-1257, 2019. [PubMed: 31538237] [Full Text: https://doi.org/10.1007/s00439-019-02063-z]
Chu, E. H. Y., Chang, C. C., Sun, N. C. Synteny of the human genes for GAL-1-PT, ACP-1, MDH-1, and GAL+-ACT and assignment to chromosome 2. Birth Defects Orig. Art. Ser. XI(3): 103-106, 1975. Note: Alternate: Cytogenet. Cell Genet. 14: 273-276, 1975. [PubMed: 1203465]
Davidson, R. G., Cortner, J. A. Genetic variant of human erythrocyte malate dehydrogenase. Nature 215: 761-762, 1967. [PubMed: 6059555] [Full Text: https://doi.org/10.1038/215761a0]
Donald, L. J. A description of human aromatic alpha-keto acid reductase. Ann. Hum. Genet. 46: 299-306, 1982. [PubMed: 6760790] [Full Text: https://doi.org/10.1111/j.1469-1809.1982.tb01581.x]
Donald, L. J. Assignment of the gene for aromatic alpha-keto acid reductase. (Abstract) Cytogenet. Cell Genet. 32: 267 only, 1982.
Friedrich, C. A., Ferrell, R. E., Siciliano, M. J., Kitto, G. B. Biochemical and genetic identity of alpha-keto acid reductase and cytoplasmic malate dehydrogenase from human erythrocytes. Ann. Hum. Genet. 52: 25-37, 1988. [PubMed: 3052244] [Full Text: https://doi.org/10.1111/j.1469-1809.1988.tb01075.x]
Friedrich, C. A., Ferrell, R. E. A population study of alpha-keto acid reductase. Ann. Hum. Genet. 49: 111-114, 1985. [PubMed: 3935039] [Full Text: https://doi.org/10.1111/j.1469-1809.1985.tb01682.x]
Friedrich, C. A., Morizot, D. C., Siciliano, M. J., Ferrell, R. E. The reduction of aromatic alpha-keto acids by cytoplasmic malate dehydrogenase and lactate dehydrogenase. Biochem. Genet. 25: 657-669, 1987. [PubMed: 2449162] [Full Text: https://doi.org/10.1007/BF00556210]
Larson, L. M., Bruce, A. W., Saumur, J. H., Wasdahl, W. A. Further evidence by gene dosage for the regional assignment of erythrocyte acid phosphatase (ACP1) and malate dehydrogenase (MDH1) loci on chromosome 2p. Clin. Genet. 22: 220-225, 1982. [PubMed: 7151307] [Full Text: https://doi.org/10.1111/j.1399-0004.1982.tb01437.x]
Leakey, T. E. B., Coward, A. R., Warlow, A., Mourant, A. E. The distribution in human populations of electrophoretic variants of cytoplasmic malate dehydrogenase. Hum. Hered. 22: 542-551, 1972. [PubMed: 4670075] [Full Text: https://doi.org/10.1159/000152536]
Shows, T. B. Genetics of human-mouse somatic cell hybrids: linkage of human genes for isocitrate dehydrogenase and malate dehydrogenase. Biochem. Genet. 7: 193-204, 1972. [PubMed: 4345850] [Full Text: https://doi.org/10.1007/BF00484817]
Tanaka, T., Inazawa, J., Nakamura, Y. Molecular cloning and mapping of a human cDNA for cytosolic malate dehydrogenase (MDH1). Genomics 32: 128-130, 1996. [PubMed: 8786100] [Full Text: https://doi.org/10.1006/geno.1996.0087]
Weil, D., Van Cong, N., Finaz, C., Rebourcet, R., Cochet, C., de Grouchy, J., Frezal, J. Localisation regionale des genes humains IDH-S, MDH-S, PGK, alpha-GAL, G6PD par l'hybridation cellulaire interspecifique. Hum. Genet. 36: 205-211, 1977. [PubMed: 870414] [Full Text: https://doi.org/10.1007/BF00273259]
Zhao, S., Xu, W., Jiang, W., Yu, W., Lin, Y., Zhang, T., Yao, J., Zhou, L., Zeng, Y., Li, H., Li, Y., Shi, J., and 10 others. Regulation of cellular metabolism by protein lysine acetylation. Science 327: 1000-1004, 2010. [PubMed: 20167786] [Full Text: https://doi.org/10.1126/science.1179689]