Alternative titles; symbols
HGNC Approved Gene Symbol: MGME1
Cytogenetic location: 20p11.23 Genomic coordinates (GRCh38): 20:17,968,590-17,991,122 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p11.23 | Mitochondrial DNA depletion syndrome 11 | 615084 | Autosomal recessive | 3 |
MGME1 is a mitochondrial RecB-type exonuclease that is essential for mitochondrial genome maintenance (Kornblum et al., 2013).
Kornblum et al. (2013) cloned human MGME1. The deduced 344-amino acid protein has an N-terminal mitochondrial targeting signal and a putative central catalytic domain similar to that of the E. coli exonuclease RecB. Fluorescence-tagged MGME1 localized to mitochondria in transfected human fibroblasts.
Using recombinant human MGME1, Kornblum et al. (2013) found that MGME1 cleaved single-stranded DNA (ssDNA) and several DNA or DNA-RNA chimeric oligonucleotides that showed free nucleic acid ends. It did not cleave single-stranded RNA, circular DNA, or double-stranded DNA containing an internal nick or gap of ssDNA. Blocking the 5-prime end, but not the 3-prime end, of ssDNA reduced the rate of cleavage. Substitution of the conserved catalytic lys253 with ala abolished all nucleolytic activities tested. Knockdown of MGME1 in HeLa cells resulted in accumulation of 7S DNA, the single-stranded component of the mtDNA displacement (D) loop that is associated with prematurely terminated mtDNA replication. Kornblum et al. (2013) concluded that MGME1 is required for effective mtDNA synthesis.
Hartz (2013) mapped the MGME1 gene to chromosome 20p11.23 based on an alignment of the MGME1 sequence (GenBank AK027503) with the genomic sequence (GRCh37).
In 5 affected members from 2 unrelated families with mitochondrial DNA depletion syndrome-11 (MTDPS11; 615084), Kornblum et al. (2013) identified a homozygous truncating mutation in the MGME1 gene (W152X; 615076.0001). The mutation was identified by exome sequencing. A second mutation (615076.0002) was identified in a German woman with a similar disorder. The phenotype was somewhat variable, but common features included ptosis, progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, severe emaciation, and respiratory insufficiency due to muscle weakness. Skeletal muscle samples from all patients showed mtDNA deletion and depletion with variable decreases in mitochondrial respiratory enzyme activity. Fibroblast cultures from 1 of the patients with the truncating mutation showed severely perturbed mtDNA replication under specific conditions with evidence of replication stalling and accumulation of replication intermediates. The findings suggested that perturbed mtDNA maintenance is the primary cause of the multisystem disorder in these patients.
Milenkovic et al. (2022) found that Mgme1 -/- mice had progressive weight loss and a shorter life span than wildtype. Aged Mgme1 -/- mice also developed altered lens and retina morphology in eye and glomerular changes and kidney inflammation, ultimately leading to severe chronic progressive nephropathy and, possibly, death due to renal failure. Mechanistically, loss of Mgme1 did not cause a defect in degradation of linear mitochondrial DNA fragments, but it led to a mitochondrial DNA replication defect where mitochondrial DNA fragments were constantly made and degraded.
In 5 affected members from 2 unrelated families with mitochondrial DNA depletion syndrome-11 (MTDPS11; 615084), Kornblum et al. (2013) identified a homozygous 456G-A transition in the MGME1 gene, resulting in a trp152-to-ter (W152X) substitution. A mutant protein could not be detected in patient fibroblasts, suggesting nonsense-mediated mRNA decay. Haplotype analysis suggested a common founder, although the families were of Lebanese and Italian descent, respectively. The mutation was identified by exome sequencing. Fibroblast cultures from 1 of the patients showed severely perturbed mtDNA replication under specific conditions with evidence of replication stalling and accumulation of replication intermediates.
In a German woman with adult-onset MTDPS11 (615084), Kornblum et al. (2013) identified a homozygous 698A-G transition in the MGME1 gene, resulting in a tyr233-to-cys (Y233C) substitution at a conserved residue.
Hartz, P. A. Personal Communication. Baltimore, Md. 2/12/2013.
Kornblum, C., Nicholls, T. J., Haack, T. B., Scholer, S., Peeva, V., Danhauser, K., Hallmann, K., Zsurka, G., Rorbach, J., Iuso, A., Wieland, T., Sciacco, M., and 13 others. Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nature Genet. 45: 214-219, 2013. [PubMed: 23313956] [Full Text: https://doi.org/10.1038/ng.2501]
Milenkovic, D., Sanz-Moreno, A., Calzada-Wack, J., Rathkolb, B., Veronica Amarie, O., Gerlini, R., Aguilar-Pimentel, A., Misic, J., Simard, M. L., Wolf, E., Fuchs, H., Gailus-Durner, V., de Angelis, M. H., Larsson, N. G. Mice lacking the mitochondrial exonuclease MGME1 develop inflammatory kidney disease with glomerular dysfunction. PLoS Genet. 18: e1010190, 2022. [PubMed: 35533204] [Full Text: https://doi.org/10.1371/journal.pgen.1010190]