Alternative titles; symbols
HGNC Approved Gene Symbol: MRPS34
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:1,771,895-1,773,134 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Combined oxidative phosphorylation deficiency 32 | 617664 | Autosomal recessive | 3 |
Mitochondria have their own translation system for production of 13 inner membrane proteins essential for oxidative phosphorylation. MRPS34 is a component of the small subunit of the mitochondrial ribosome that is encoded by the nuclear genome (Koc et al., 2001).
By proteolytic digestion of whole bovine 28S subunits, followed by peptide analysis and EST database analysis, O'Brien et al. (2000) and Koc et al. (2001) independently identified full-length human MRPS34, which O'Brien et al. (2000) called MRPS12. The deduced protein contains 218 amino acids. Koc et al. (2001) determined that the MRPS34 protein has a calculated molecular mass of 25.7 kD. Removal of a predicted N-terminal 18-amino acid mitochondrial localization signal results in a mature 23.6-kD protein. O'Brien et al. (2000) also identified a possible splice variant of MRPS34. O'Brien et al. (2000) and Koc et al. (2001) identified MRPS34 orthologs in mouse, rat, Drosophila, and C. elegans, but not in yeast or E. coli. Koc et al. (2001) reported that mouse and human MRPS34 share 86.5% amino acid identity.
Using Western blot analysis, Richman et al. (2015) detected variable Mrps34 expression in all 10 mouse tissues examined.
O'Brien et al. (2000) determined that the MRPS34 gene contains 4 exons and spans approximately 1.5 kb.
By genomic sequence analysis, O'Brien et al. (2000) mapped the MRPS34 gene to chromosome 16q13-q21.
Richman et al. (2015) reported that the mouse Mrps34 gene maps to chromosome 17.
In 6 patients from 4 unrelated families with combined oxidative phosphorylation deficiency-32 (COXPD32; 617664), Lake et al. (2017) identified homozygous or compound heterozygous mutations in the MRPS34 gene (611994.0001-611994.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients cells showed decreased levels of MRPS34 protein, consistent with a loss of function, variably decreased activities of mitochondrial respiratory complexes I, III, and IV, and a defect in mitochondrial translation. Patient cells showed decreased levels and assembly of small mitoribosome subunit proteins with sparing of the large subunit; these findings were consistent with destabilization of the small subunit. Expression of wildtype MRPS34 rescued these cellular defects.
Richman et al. (2015) characterized a mouse line carrying an N-ethyl-N-nitrosourea-induced 203T-C mutation in the Mrps34 gene. The mutation, which changed the conserved leu68 to pro, reduced, but did not eliminate, Mrps34 expression in all 10 mouse tissues examined. Mrps34 mutant mice appeared normal at birth, but they developed heart hypertrophy, increased fractional shortening, and reduced oxygen consumption. They also showed liver steatosis and variable physiologic changes in multiple tissues, including eye. Western blot analysis showed that mutant Mrps34 associated normally with 12S ribosomal RNA (rRNA), but that aged mutant mice had reduced content of both 12S rRNA and the large rRNA subunit in heart and liver, reduced mitochondrial content of nuclear-encoded proteins, and reduced mitochondrial protein synthesis, including synthesis of respiratory complexes.
In a patient (S1), born of consanguineous Italian parents, with combined oxidative phosphorylation deficiency-32 (COXPD32; 617664), Lake et al. (2017) identified a homozygous G-to-T transversion (c.321+1G-T, NM_023936.1) in intron 1 of the MRPS34 gene, predicted to result in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP or gnomAD databases. Studies of patient cells showed that the mutation resulted in an in-frame deletion of 8 highly conserved amino acids (Val100_Gln107del). Immunoblot analysis of patient tissues showed absent or markedly decreased levels of MRPS34 protein, suggesting degradation of the mutant protein.
In 4 patients (S2a/b, S3a/b) from 2 unrelated families of Puerto Rican descent with combined oxidative phosphorylation deficiency-32 (COXPD32; 617664), Lake et al. (2017) identified a homozygous G-to-A transition (c.322-10G-A, NM_023936.1) in intron 2 of the MRPS34 gene, predicted to result in abnormal gene splicing and creation of a new cryptic splice acceptor site in intron 1. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was reported in the dbSNP database and in heterozygous state in 2 individuals of Latino ancestry in the gnomAD database (2 of 236,804 alleles). Haplotype analysis of the 2 affected families suggested a founder effect. Analysis of patient cells showed that the mutation resulted in 2 abnormal transcripts: about 68 to 80% of the transcripts represented a frameshift and premature termination (Asn108LeufsTer12), 10 to 18% of the transcripts represented the skipping of exon 2 (Asn108GlyfsTer50), and 10 to 15% of the transcripts represented wildtype. There was a 75% reduction in MRPS34 transcripts in patient cells, suggesting that this is a hypomorphic mutation. Patient cells also showed significantly decreased protein levels compared to controls.
In a patient (S4), born of unrelated French parents, with combined oxidative phosphorylation deficiency-32 (COXPD32; 617664), Lake et al. (2017) identified compound heterozygous mutations in the MRPS34 gene: a c.37G-A transition (c.37G-A, NM_023936.1), resulting in a glu13-to-lys (E13K) substitution at a highly conserved residue, and a c.94C-T transition, resulting in a gln32-to-ter (Q32X; 611994.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The E13K mutation was not found in the dbSNP or gnomAD databases. The Q32X variant was reported in the dbSNP database and in heterozygous state in 39 of 82,878 alleles in the gnomAD database. Patient cells showed significantly decreased protein levels compared to controls.
For discussion of the c.94C-T transition (c.94C-T, NM_023936.1) in the MRPS34 gene, resulting in a gln32-to-ter (Q32X) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-32 (COXPD32; 617664) by Lake et al. (2017), see 611994.0003.
Koc, E., Burkhart, W., Blackburn, K., Moseley, A., Spremulli, L. L. The small subunit of the mammalian mitochondrial ribosome: identification of the full complement of ribosomal proteins present. J. Biol. Chem. 276: 19363-19374, 2001. [PubMed: 11279123] [Full Text: https://doi.org/10.1074/jbc.M100727200]
Lake, N. J., Webb, B. D., Stroud, D. A., Richman, T. R., Ruzzenente,B., Compton, A. G., Mountford, H. S., Pulman, J., Zangarelli, C., Rio, M., Boddaert, N., Assouline, Z., and 19 others. Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and Leigh syndrome. Am. J. Hum. Genet. 101: 239-254, 2017. Note: Erratum: Am. J. Hum. Genet. 102: 713 only, 2018. [PubMed: 28777931] [Full Text: https://doi.org/10.1016/j.ajhg.2017.07.005]
O'Brien, T. W., Liu, J., Sylvester, J. E., Mougey, E. B., Fischel-Ghodsian, N., Thiede, B., Wittmann-Liebold, B., Graack, H.-R. Mammalian mitochondrial ribosomal proteins (4): amino acid sequencing, characterization, and identification of corresponding gene sequences. J. Biol. Chem. 275: 18153-18159, 2000. [PubMed: 10751423] [Full Text: https://doi.org/10.1074/jbc.M909762199]
Richman, T. R., Ermer, J. A., Davies, S. M. K., Perks, K. L., Viola, H. M., Shearwood, A.-M. J., Hool, L. C., Rackham, O., Filipovska, A. Mutation in MRPS34 compromises protein synthesis and causes mitochondrial dysfunction. PLoS Genet. 11: e1005089, 2015. Note: Electronic Article. [PubMed: 25816300] [Full Text: https://doi.org/10.1371/journal.pgen.1005089]