Alternative titles; symbols
HGNC Approved Gene Symbol: MDH2
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:76,048,106-76,067,508 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.23 | Developmental and epileptic encephalopathy 51 | 617339 | Autosomal recessive | 3 |
The MDH2 gene encodes the Krebs cycle enzyme mitochondrial malate dehydrogenase, which catalyzes the reversible oxidation of malate to oxaloacetate and plays a role in the malate-aspartate NADH shuttle (summary by Ait-El-Mkadem et al., 2017).
See also cytoplasmic MDH1 (154200).
From study of hybrid cells, Van Heyningen et al. (1975) mapped the locus for MDH2 to chromosome 7. Habets et al. (1992) subsequently mapped the locus to 7cen-q22.
Gross (2017) mapped the MDH2 gene to chromosome 7q11.23 based on an alignment of the MDH2 sequence (GenBank AF047470) with the genomic sequence (GRCh38).
In 3 unrelated boys with developmental and epileptic encephalopathy-51 (DEE51; 617339), Ait-El-Mkadem et al. (2017) identified compound heterozygous mutations in the MDH2 gene (154100.0001-154100.0004). Functional studies in fibroblasts from 2 patients showed a loss of MDH2 protein and almost undetectable MDH2 enzymatic activity, which could be restored by wildtype MDH2. Patient cells showed accumulation of the MDH2 substrates malate and fumarate. Expression of the homologous mutations into yeast resulted in a growth defect, supporting the pathogenicity. However, patient cells did not show substantial defects in mitochondrial respiratory chain activity, and the mitochondrial filamentous network appeared normal.
Priestley et al. (2022) reported biallelic mutations in the MDH2 gene in 7 patients, including a sib pair, from 6 families with DEE51. Patient A had compound heterozygous mutations (P133L, 154100.0001 and D173N, 154100.0005). Patients B and C, who were unrelated Indian patients, had a homozygous splicing mutation (c.855+5G-A; 154100.0006). Patients E and F, Afghan sibs who were born to consanguineous parents, had a homozygous missense mutation (M251V; 154100.0007). Patient D had homozygosity for a G360S mutation, but the allele frequency for this variant in the gnomAD database was 0.36%, with 4 homozygotes reported, making its pathogenicity questionable. Patient G had homozygosity for an A66T mutation, but familial segregation studies were not completed, making its pathogenicity questionable.
Associations Pending Confirmation
By exome sequencing in 60 families from the US and Italy with type 2 diabetes (T2D; see 125853) in a pattern consistent with autosomal dominant inheritance but unlinked to mutations in genes known to be associated with maturity-onset diabetes of the young (MODY; see 606391), Jungtrakoon Thamtarana et al. (2022) identified 2 families with heterozygous mutations in the MDH2 gene. Seven of 8 members with hyperglycemia from family 1 had an arg52-to-cys (R52C, c.154C-T, NM_005918.2) mutation. The age of onset of prediabetes or diabetes in the affected family members was 2 to 58 years. One family member, aged 16 years, had the mutation but did not have hyperglycemia. The mutation was present in the gnomAD database (v3.1.1) in 1 of 152,116 alleles. Four members from family 2 with abnormal glucose homeostasis had a val160-to-met (V160M, c.478G-A, NM_005918.2) mutation. The mutation was also detected in 6 unaffected family members. The mutation was present in the gnomAD database (v3.1.1) at an allele frequency of 0.0003 in non-Finnish Europeans. HepG2 cells were transfected with MDH2 with each of the mutations, and both mutations resulted in increased MDH2 enzyme activity and lower NAD+/NADH compared to wildtype. Expression of each mutation in a mouse insulinoma cell line (MIN6-K8) resulted in decreased glucose-stimulated insulin secretion compared to wildtype. Jungtrakoon Thamtarana et al. (2022) concluded that the R52C and V160M mutations result in gain-of-function effects and glucose dyshomeostasis.
In both leukocytes and placentas, Davidson and Cortner (1967) found polymorphism of the malate dehydrogenase that is bound to mitochondria, called M-MDH originally and now symbolized MDH2. The fact that mitochondrial malate dehydrogenase was indistinguishable from normal in persons with variation in the supernatant MDH indicates that a separate locus is involved in its genetic determination. Mendelian segregation rather than maternal inheritance of MDH2 suggests that not all mitochondrial proteins are coded by mitochondrial DNA. Mitochondrial glutamic oxaloacetic transaminase (138150) is also determined by nuclear genes.
In 3 unrelated boys (SCV000321300, SCV000322707, SCV000299301) with developmental and epileptic encephalopathy-51 (DEE51; 617339), Ait-El-Mkadem et al. (2017) identified compound heterozygous mutations in the MDH2 gene. All 3 patients carried a c.398C-T transition (c.398C-T, NM_005918.3) resulting in a pro133-to-leu (P133L) substitution, on 1 allele. Patient 1 carried a c.620C-T transition, resulting in a pro207-to-leu (P207L; 154100.0002) on the other allele; patient 2 carried a 1-bp deletion (c.596delG; 154100.0003), resulting in a frameshift and premature termination (Gly199AlafsTer10) on the other allele; and patient 3 carried a de novo c.109G-A transition, resulting in a gly37-to-arg (G37R; 154100.0004) substitution in the NAD binding pocket on the other allele. All missense mutations occurred at highly conserved residues. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. The c.398C-T transition was found 7 times in the heterozygous state in the ExAC database, the c.109G-A transition was found 2 times in the heterozygous state in the ExAC database, and the c.620C-T transition was absent from public databases. The patients had onset of refractory seizures between birth and the first months of life. One patient died at 1.5 years of age secondary to metabolic decompensation.
In a patient (patient A) with DEE51, Priestley et al. (2022) identified compound heterozygous mutations in the MDH2 gene: P133L and a c.517G-A transition resulting in an asp173-to-asn (D173N; 154100.0005) substitution. The mutations, which were identified by trio whole-exome sequencing, were present in the carrier state in the parents. The P133L mutation was present in the gnomAD database at an allele frequency of 0.0052%, and the D173N mutation was present at an allele frequency of 0.0028%. Fibroblast MDH2 activity was reduced in the patient compared to controls.
For discussion of the c.620C-T transition (c.620C-T, NM_005918.3) in the MDH2 gene, resulting in a pro207-to-leu (P207L) substitution, that was found in compound heterozygous state in a patient (SCV000321301) with developmental and epileptic encephalopathy-51 (DEE51; 617339) by Ait-El-Mkadem et al. (2017), see 154100.0001.
For discussion of the 1-bp deletion (c.596delG, NM_005918.3) in the MDH2 gene, resulting in a frameshift and premature termination (Gly199AlafsTer10), that was found in compound heterozygous state in a patient (SCV000322708) with developmental and epileptic encephalopathy-51 (DEE51; 617339) by Ait-El-Mkadem et al. (2017), see 154100.0001.
For discussion of the c.109G-A transition (c.109G-A, NM_005918.3) in the MDH2 gene, resulting in a gly37-to-arg (G37R) substitution, that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-51 (DEE51; 617339) by Ait-El-Mkadem et al. (2017), see 154100.0001.
For discussion of the c.517G-A transition in exon 5 of the MDH2 gene, resulting in an asp173-to-asn (D173N) substitution, that was identified in compound heterozygous state in a patient (patient A) with developmental and epileptic encephalopathy-51 (DEE51; 617339) by Priestley et al. (2022), see 154100.0001.
In 2 unrelated Indian patients (patients B and C) with developmental and epileptic encephalopathy-51 (DEE51; 617339), Priestley et al. (2022) identified homozygosity for a c.855+5G-A transition in intron 8 of the MDH2 gene. The mutation was identified by whole-exome sequencing in both patients. The allele frequency of this mutation in the gnomAD database was 0.0044%. Functional studies in patient cells were not performed.
In 2 sibs (patients E and F), born to consanguineous Afghan parents, with developmental and epileptic encephalopathy-51 (DEE51; 617339), Priestley et al. (2022) identified homozygosity for a c.751A-G transition in exon 8 of the MDH2 gene, resulting in a met251-to-val (M251V) substitution. The mutation was identified by whole-exome sequencing and segregated with disease in the family. The allele frequency of the M251V mutation in population databases was 0.0004%.
Ait-El-Mkadem, S., Dayem-Quere, M., Gusic, M., Chaussenot, A., Bannwarth, S., Francois, B., Genin, E. C., Fragaki, K., Volker-Touw, C. L. M., Vasnier, C., Serre, V., van Gassen, K. L. I., and 24 others. Mutations in MDH2, encoding a Krebs cycle enzyme, cause early-onset severe encephalopathy. Am. J. Hum. Genet. 100: 151-159, 2017. [PubMed: 27989324] [Full Text: https://doi.org/10.1016/j.ajhg.2016.11.014]
Benn, P., Chern, C. J., Bruns, G., Craig, I. W., Croce, C. M. Assignment of the genes for human beta-glucuronidase and mitochondrial malate dehydrogenase to the region pter-q22 of chromosome 7. Cytogenet. Cell Genet. 19: 273-280, 1977. [PubMed: 606506] [Full Text: https://doi.org/10.1159/000130820]
Blake, N. M. Malate dehydrogenase types in the Asian-Pacific area, and a description of new phenotypes. Hum. Genet. 43: 69-80, 1978. [PubMed: 669720] [Full Text: https://doi.org/10.1007/BF00396480]
Davidson, R. G., Cortner, J. A. Mitochondrial malate dehydrogenase: a new genetic polymorphism in man. Science 157: 1569-1571, 1967. [PubMed: 6038170] [Full Text: https://doi.org/10.1126/science.157.3796.1569]
Gross, M. B. Personal Communication. Baltimore, Md. 2/10/2017.
Habets, G. G. M., van der Kammen, R. A., Willemsen, V., Balemans, M., Wiegant, J., Collard, J. G. Sublocalization of an invasion-inducing locus and other genes on human chromosome 7. Cytogenet. Cell Genet. 60: 200-205, 1992. [PubMed: 1505215] [Full Text: https://doi.org/10.1159/000133336]
Jungtrakoon Thamtarana, P., Marucci, A., Pannone, L., Bonnefond, A., Pezzilli, S., Biagini, T., Buranasupkajorn, P., Hastings, T., Mendonca, C., Marselli, L., Di Paola, R., Abubakar, Z., and 14 others. Gain of function of malate dehydrogenase 2 and familial hyperglycemia. J. Clin. Endocr. Metab. 107: 668-684, 2022. [PubMed: 34718610] [Full Text: https://doi.org/10.1210/clinem/dgab790]
Priestley, J. R. C., Pace, L. M., Sen, K., Aggarwal, A., Alves, C. A. P. F., Campbell, I. M., Cuddapah, S. R., Engelhardt, N. M., Eskandar, M., Jolin Garcia, P. C., Gropman, A., Helbig, I., Hong, X., Gowda, V. K., Lusk, L., Trapane, P., Srinivasan, V. M., Suwannarat, P., Ganetzky, R. D. Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature. Molec. Genet. Metab. Rep. 33: 100931, 2022. [PubMed: 36420423] [Full Text: https://doi.org/10.1016/j.ymgmr.2022.100931]
Shimizu, N., Shimizu, Y., Ruddle, F. H. Assignment of the human mitochondrial NAD-linked malate dehydrogenase gene to the p22-qter region of chromosome 7. Cytogenet. Cell Genet. 22: 441-445, 1978. [PubMed: 222545] [Full Text: https://doi.org/10.1159/000130992]
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]
Van Heyningen, V., Bobrow, M., Bodmer, W. F., Gardiner, S. E., Povey, S., Hopkinson, D. A. Chromosome assignment of some human enzyme loci: mitochondrial malate dehydrogenase to 7, mannosephosphate isomerase and pyruvate kinase to 15 and probably, esterase D to 13. Ann. Hum. Genet. 38: 295-303, 1975. [PubMed: 1137344] [Full Text: https://doi.org/10.1111/j.1469-1809.1975.tb00613.x]