Alternative titles; symbols
HGNC Approved Gene Symbol: MRM2
Cytogenetic location: 7p22.3 Genomic coordinates (GRCh38) : 7:2,234,195-2,242,205 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p22.3 | Mitochondrial DNA depletion syndrome 17 | 618567 | Autosomal recessive | 3 |
By database searching for EST clones corresponding to a genomic sequence identified by Jin et al. (1999), Ching et al. (2002) identified FTSJ2, a human homolog of E. coli FtsJ2. The deduced 246-amino acid protein has a calculated molecular mass of 27.4 kD and contains a methyltransferase domain. An iterative search of all available DNA sequences suggested that FTSJ2 is a member of a large and diverse family of evolutionarily conserved S-adenosylmethionine-binding proteins from bacteria to human, which contains at least 180 members. Northern blot analysis detected a 1.7-kb transcript in most tissues, with highest expression in muscle, placenta, and heart. A 2.6-kb transcript, which may represent a splice variant, was detected in heart. Both transcripts were found in all cancer cells tested. Ching et al. (2002) localized fluorescence-tagged FTSJ2 to the nucleolus of transiently transfected HeLa cells.
Ching et al. (2002) determined that the FTSJ2 gene spans about 8 kb and has 3 exons.
By radiation hybrid analysis, Jin et al. (1999) mapped the FTSJ2 gene to chromosome 7p22.
Using targeted exome sequencing of mitochondrial proteins and mitochondrial DNA, Garone et al. (2017) identified a homozygous missense mutation in the MRM2 gene (G189R; 606906.0001) in a boy with a MELAS-like mitochondrial depletion syndrome, mitochondrial depletion syndrome-17 (MTDPS17; 618567). The glycine at position 189 was conserved in 41 of 44 vertebrate species tested and in S. cerevisiae and E. coli as well. In a yeast model, defects in cellular respiration and modification of a human-equivalent uridine were rescued by complementation with wildtype yeast mrm2, but not by mrm2 carrying a mutation homologous to that carried by the patient.
Shafique et al. (2023) identified homozygous mutations in the MRM2 gene in patients from 2 families with MTDPS17: in family DYAF11, 4 sibs, born to consanguineous Pakistani parents, had a splice site mutation (c.8+1G-T, 606906.0002), and in family M, 2 sibs, born to nonconsanguineous Montenegrin parents, had a missense mutation (A81V, 606906.0003). The mutations were identified by whole-exome sequencing and segregated with disease in each family.
Garone et al. (2017) reported a boy with mitochondrial depletion syndrome 17 (MTDPS17; 618567) who was homozygous for a G-to-A transition at nucleotide 567 of the MRM2 gene (c.567G-A, NM_013393) resulting in a gly-to-arg substitution at codon 189 (G189R). This variant was not found in gnomAD. The G189R mutation was found in a 16-kb run of homozygosity and was carried in heterozygosity by both parents. Glycine-189 was conserved in 41 of 44 vertebrate species tested and in S. cerevisiae and E. coli as well. Garone et al. (2017) generated a knockout yeast model for the orthologous gene that showed a defect in respiration and the reduction of 2-prime-O-methyl modification at the position in the yeast mitochondrial 21S rRNA equivalent to the position in the human 16S rRNA that is 2-prime-O-methylated by MRM2. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead completely rescued by expressing the wildtype allele.
In 4 sibs, born to consanguineous Pakistani parents (family DYAF11), with mitochondrial depletion syndrome 17 (MTDPS17; 618567), Shafique et al. (2023) identified homozygosity for a c.8+1G-T transversion (c.8+1G-T, NM_013393.1) in the MRM2 gene, predicted to result in abnormal splicing. The mutation, which was identified by linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The mutation was present in the gnomAD database at an allele frequency of 0.00002 and was not present in a database of 200 Pakistani controls. Sequencing of cDNA from blood of the 4 patients demonstrated that the mutation resulted in both normal and abnormal splicing transcripts.
In 2 sibs, born of nonconsanguineous Montenegrin parents (family M), with mitochondrial depletion syndrome 17 (MTDPS17; 618567), Shafique et al. (2023) identified homozygosity for a c.242C-T transition (c.242C-T, NM_013393.1) in the MRM2 gene, resulting in an ala81-to-val (A81V) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The mutation was present in the gnomAD database at an allele frequency of 0.00001997. Functional studies in patient cells were not performed.
Ching, Y.-P., Zhou, H.-J., Yuan, J.-G., Qiang, B.-Q., Kung, H., Jin, D.-Y. Identification and characterization of FTSJ2, a novel human nucleolar protein homologous to bacterial ribosomal RNA methyltransferase. Genomics 79: 2-6, 2002. [PubMed: 11827451] [Full Text: https://doi.org/10.1006/geno.2001.6670]
Garone, C., D'Souza, A. R., Dallabona, C., Lodi, T., Rebelo-Guiomar, P., Rorbach, J., Donati, M. A., Procopio, E., Montomoli, M., Guerrini, R., Zeviani, M., Calvo, S. E., Mootha, V. K., DiMauro, S., Ferrero, I., Minczuk, M. Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome. Hum. Molec. Genet. 26: 4257-4266, 2017. [PubMed: 28973171] [Full Text: https://doi.org/10.1093/hmg/ddx314]
Jin, D.-Y., Kozak, C. A., Pangilinan, F., Spencer, F., Green, E. D., Jeang, K.-T. Mitotic checkpoint locus MAD1L1 maps to human chromosome 7p22 and mouse chromosome 5. Genomics 55: 363-364, 1999. [PubMed: 10049595] [Full Text: https://doi.org/10.1006/geno.1998.5654]
Shafique, A., Arif, B., Chu, M. L., Moran, E., Hussain, T., Zamora, F. M., Wohler, E., Sobreira, N., Klein, C., Lohmann, K., Naz, S. MRM2 variants in families with complex dystonic syndromes: evidence for phenotypic heterogeneity. J. Med. Genet. 60: 352-358, 2023. [PubMed: 36002240] [Full Text: https://doi.org/10.1136/jmg-2022-108521]