MRPS22 (mS22, human, UniProt P82650): research report

Identity check

The symbol, protein and organism match. MRPS22 (synonyms C3orf5, RPMS22, GK002) encodes the 360-aa "Small ribosomal subunit protein mS22" (28S ribosomal protein S22, mitochondrial). It is Homo sapiens (taxon 9606), in the mitochondrion-specific ribosomal protein mS22 family, with the InterPro domain IPR019374 (Ribosomal_mS22) and the Pfam family PF10245 (MRP-S22). I found no ambiguity with another gene. The following come from the local UniProt record (MRPS22-uniprot.txt, entry version 194). The first two cite PMID:25838379 and PMID:17873122 as given there. The disease entries (COXPD5, ODG7) are quoted from the record.

Scope of this report. I ran two web searches, one on disease and one on mitoribosome structure. The structure search did not return anything specific to mS22. Some statements below come from my background knowledge and are flagged as not verified in this session.

Primary function

MRPS22 is a structural protein, not an enzyme or signalling protein. It is a component of the mitochondrial small ribosomal subunit (mt-SSU, 28S).

• UniProt describes the mammalian 55S mitoribosome as a 28S small subunit and a 39S large subunit. The 28S subunit contains the 12S mt-rRNA and 30 different proteins. The 39S subunit contains 16S mt-rRNA, mt-tRNA(Val) and 52 proteins. UniProt cites PMID:25838379 (Greber & Ban, structure of the human mitoribosome) for this. The UniProt record gives the protein's location as "Mitochondrion", also citing PMID:25838379.
• The mitoribosome translates the 13 mtDNA-encoded OXPHOS subunits. Amunts et al. 2015 (Science, cryo-EM at 3.5 Å, PDB 3J9M) reported 80 proteins and three rRNAs. They also described extensive remodelling of the small-subunit head around the mRNA channel (PMC4501431; RCSB 3J9M). That search result did not mention mS22 specifically.
• From background knowledge, not verified here: mS22 is a mitochondria-specific small-subunit protein. It sits in the body of the 28S subunit and contributes to rRNA scaffolding and assembly, and it has no bacterial orthologue.
• UniProt lists one IntAct interaction, with MRPS18B (Q9Y676), which is another mt-SSU protein. That is consistent with co-assembly in the same particle and does not indicate an independent function.

For GO curation.
- The appropriate molecular function is structural constituent of ribosome (GO:0003735).
- The component terms are mitochondrial small ribosomal subunit (GO:0005763) and the mitochondrion.
- The process is mitochondrial translation (GO:0032543). It is supported indirectly, as the ribosome's function. No catalytic step is attributed to mS22 itself.
- The GOA file also contains protein binding (GO:0005515, two rows with an experimental ECO code). This is uninformative and should be replaced by, or subsumed under, the structural constituent annotation.
- GOA has many mitochondrial inner membrane rows (GO:0005743, ECO:0000304, TAS-type, apparently from Reactome). The mitoribosome is membrane-associated in vivo, but this is a weak annotation for an individual protein and is better treated as non-core. I did not check this against the primary literature.

Localisation

The protein is in the mitochondrial matrix side of the inner membrane, as part of the mitoribosome. UniProt lists the location as mitochondrion, and GOA has an HPA IDA mitochondrion annotation. The exact sub-mitochondrial location comes from the structural context and was not examined in this session.

Pathway

The relevant pathway is mitochondrial translation. The ribosome synthesises the 13 mtDNA-encoded subunits of OXPHOS complexes I, III, IV and V, so mS22 deficiency causes combined OXPHOS defects.

Disease evidence (loss-of-function)

These studies show the protein is necessary for mitochondrial translation. They are not evidence of a catalytic role.

• COXPD5 (MIM 611719). UniProt describes it as severe metabolic acidosis, edema, hypertrophic cardiomyopathy, tubulopathy and hypotonia. Smits et al. 2010 reported a patient with Cornelia de Lange-like features, brain abnormalities, hypertrophic cardiomyopathy and combined complex I, III and IV deficiency. The patient was homozygous for a variant predicted to give Leu215Pro. Re-expressing wild-type MRPS22 in patient fibroblasts restored complex IV amount and activity and 12S rRNA levels (PMC; EJHG 2010). The 12S rRNA result is consistent with a role in small-subunit stability or assembly.
• Severe neonatal case. Baertling et al. 2015 reported a neonate with fatal lactic acidosis and combined OXPHOS deficiency, a homozygous MRPS22 mutation, agenesis of the corpus callosum, and atrial and ventricular septal defects with a coronary artery fistula (Springer).
• Ovarian dysgenesis 7 (MIM 618117). UniProt cites PMID:29566152 for an autosomal recessive form with streak gonads and primary amenorrhea. GeneCards also lists 46,XX gonadal dysgenesis (GeneCards). I did not read the primary paper.
• The UniProt record cites PMID:17873122 for the COXPD5 entry. I did not check that paper, and it may be an earlier MRPS22 mutation report.

Evidence summary

Gaps and caveats

• I did not retrieve PMID:25838379, PMID:17873122 or PMID:29566152 to confirm what they show for MRPS22. Check the cached publications/PMID_*.md files before using them as evidence in the review.
• The precise position of mS22 within the 28S subunit (which rRNA helices and neighbouring proteins it contacts) needs the structure papers or PDB 3J9M, which this session did not cover.
• There is no evidence of any non-ribosomal function. The unexplained pleiotropy (cardiomyopathy, brain malformations, ovarian dysgenesis) is best attributed to tissue-specific dependence on mitochondrial translation.

Sources:
- Smits et al. 2010, PMC
- Smits et al. 2010, EJHG
- Baertling et al. 2015
- GlyCosmos COXPD5
- GeneCards MRPS22
- Amunts et al. 2015, PMC4501431
- RCSB PDB 3J9M
- Local files: genes/human/MRPS22/MRPS22-uniprot.txt, MRPS22-goa.tsv

Citations

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC4501431
2. https://www.rcsb.org/structure/3J9M
3. https://pmc.ncbi.nlm.nih.gov/articles/pmid/21189481
4. https://www.nature.com/articles/ejhg2010214
5. https://link.springer.com/article/10.1007/s10048-015-0440-6
6. https://www.genecards.org/card/MRPS22
7. https://glycosmos.org/diseases/DOID:0111473