MRPS22

Summary

MRPS22 (mitochondrial ribosomal protein S22, HGNC:14508) is a protein-coding gene on chromosome 3q23, encoding Small ribosomal subunit protein mS22 (P82650). It is a selective cancer dependency (DepMap: 60.8% of cell lines).

Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that does not seem to have a counterpart in prokaryotic and fungal-mitochondrial ribosomes. This gene lies telomeric of and is transcribed in the opposite direction from the forkhead box L2 gene. A pseudogene corresponding to this gene is found on chromosome Xq.

Source: NCBI Gene 56945 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 217 total — 13 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 61
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 60.8% of screened cell lines
• MANE Select transcript: NM_020191

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14508
Approved symbol	MRPS22
Name	mitochondrial ribosomal protein S22
Location	3q23
Locus type	gene with protein product
Status	Approved
Aliases	MRP-S22, GK002, C3orf5, GIBT, mS22
Ensembl gene	ENSG00000175110
Ensembl biotype	protein_coding
OMIM	605810
Entrez	56945

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 16 protein_coding, 6 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000310776, ENST00000465373, ENST00000466690, ENST00000478464, ENST00000480644, ENST00000480938, ENST00000483545, ENST00000486705, ENST00000489521, ENST00000492644, ENST00000495075, ENST00000495225, ENST00000498505, ENST00000680020, ENST00000684961, ENST00000686433, ENST00000687538, ENST00000688328, ENST00000688697, ENST00000689286, ENST00000689925, ENST00000690298, ENST00000691070, ENST00000692727, ENST00000693155, ENST00000871206, ENST00000871207, ENST00000938299, ENST00000964892

RefSeq mRNA: 3 — MANE Select: NM_020191 NM_001363857, NM_001363893, NM_020191

CCDS: CCDS3107, CCDS87143

Canonical transcript exons

ENST00000680020 — 8 exons

Exon	Start	End
ENSE00001317429	139344020	139344198
ENSE00001323614	139356919	139357129
ENSE00003516723	139346878	139347044
ENSE00003550410	139348160	139348324
ENSE00003576752	139350179	139350322
ENSE00003584386	139355682	139355790
ENSE00003674716	139350977	139351060
ENSE00003789463	139352647	139352792

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 65.5799 / max 376.7165, expressed in 1825 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38823	63.2429	1825
38824	0.9587	582
38820	0.6987	241
38825	0.3532	163
38822	0.2954	107
38821	0.0311	17

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.18	gold quality
right adrenal gland	UBERON:0001233	96.61	gold quality
right adrenal gland cortex	UBERON:0035827	96.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.43	gold quality
calcaneal tendon	UBERON:0003701	96.31	gold quality
tibialis anterior	UBERON:0001385	96.26	gold quality
left adrenal gland	UBERON:0001234	96.12	gold quality
endothelial cell	CL:0000115	96.07	gold quality
left ventricle myocardium	UBERON:0006566	95.98	gold quality
adrenal gland	UBERON:0002369	95.80	gold quality
deltoid	UBERON:0001476	95.77	gold quality
left adrenal gland cortex	UBERON:0035825	95.71	gold quality
tendon	UBERON:0000043	95.68	gold quality
adrenal cortex	UBERON:0001235	95.52	gold quality
muscle of leg	UBERON:0001383	95.51	gold quality
heart right ventricle	UBERON:0002080	95.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.41	gold quality
gastrocnemius	UBERON:0001388	95.38	gold quality
muscle organ	UBERON:0001630	95.25	gold quality
skeletal muscle organ	UBERON:0014892	95.25	gold quality
middle temporal gyrus	UBERON:0002771	95.18	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.05	gold quality
biceps brachii	UBERON:0001507	95.01	gold quality
quadriceps femoris	UBERON:0001377	94.79	gold quality
heart left ventricle	UBERON:0002084	94.76	gold quality
cardiac ventricle	UBERON:0002082	94.73	gold quality
vastus lateralis	UBERON:0001379	94.66	gold quality
esophagus squamous epithelium	UBERON:0006920	94.37	gold quality
diaphragm	UBERON:0001103	94.29	gold quality
skeletal muscle tissue	UBERON:0001134	94.28	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.34
E-MTAB-7249	no	459.62

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 60.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• A mutation in the MRPS22 gene led to reduction of 12sRNA in fibroblasts and fatal neonatal hypertrophic cardiomyopathy & kidney tubulopathy. (PMID:17873122)
• The effect of mutated MRPS22 on the assembly of the small and large ribosomal subunits in human mitochondria is reported. (PMID:18539099)
• hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22 (PMID:28752220)
• Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of Primary ovarian insufficiency in adolescents. (PMID:29566152)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mrps22	ENSDARG00000018073
mus_musculus	Mrps22	ENSMUSG00000032459
rattus_norvegicus	Mrps22	ENSRNOG00000047984
drosophila_melanogaster	mRpS22	FBGN0039555
caenorhabditis_elegans		WBGENE00007564

Protein

Protein identifiers

Small ribosomal subunit protein mS22 — P82650 (reviewed: P82650)

Alternative names: 28S ribosomal protein S22, mitochondrial

All UniProt accessions (11): A0A7P0MKV3, A0A8I5KQ79, A0A8I5KQR7, A0A8I5KSY5, A0A8I5KX02, A0A8I5KYF1, P82650, G5E9W7, H7C5F2, H7C5H3, H7C5L9

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.

Subcellular location. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 5 (COXPD5) [MIM:611719] A mitochondrial disease resulting in severe metabolic acidosis, edema, hypertrophic cardiomyopathy, tubulopathy, and hypotonia. The disease is caused by variants affecting the gene represented in this entry. Ovarian dysgenesis 7 (ODG7) [MIM:618117] A form of ovarian dysgenesis, a disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. ODG7 is an autosomal recessive condition. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the mitochondrion-specific ribosomal protein mS22 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P82650-1	1	yes
P82650-2	2

RefSeq proteins (3): NP_001350786, NP_001350822, NP_064576* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019374	Ribosomal_mS22	Family

Pfam: PF10245

UniProt features (34 total): helix 17, strand 7, splice variant 3, sequence variant 3, modified residue 2, chain 1, turn 1

Structure

Experimental structures (PDB)

77 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7QI4	ELECTRON MICROSCOPY	2.21
8CSS	ELECTRON MICROSCOPY	2.36
7P2E	ELECTRON MICROSCOPY	2.4
8RRI	ELECTRON MICROSCOPY	2.4
9OLF	ELECTRON MICROSCOPY	2.46
9OJM	ELECTRON MICROSCOPY	2.5
8CSQ	ELECTRON MICROSCOPY	2.54
8CSR	ELECTRON MICROSCOPY	2.54
6ZM6	ELECTRON MICROSCOPY	2.59
7QI5	ELECTRON MICROSCOPY	2.63
8CSP	ELECTRON MICROSCOPY	2.66
7PNX	ELECTRON MICROSCOPY	2.76
8ANY	ELECTRON MICROSCOPY	2.85
8CST	ELECTRON MICROSCOPY	2.85
6ZM5	ELECTRON MICROSCOPY	2.89
7PO0	ELECTRON MICROSCOPY	2.9
8K2A	ELECTRON MICROSCOPY	2.9
9PGL	ELECTRON MICROSCOPY	2.9
7PO1	ELECTRON MICROSCOPY	2.92
7PO3	ELECTRON MICROSCOPY	2.92
9PGF	ELECTRON MICROSCOPY	2.93
6VMI	ELECTRON MICROSCOPY	2.96
6RW4	ELECTRON MICROSCOPY	2.97
6VLZ	ELECTRON MICROSCOPY	2.97
7QI6	ELECTRON MICROSCOPY	2.98
8QRN	ELECTRON MICROSCOPY	2.98
9PSM	ELECTRON MICROSCOPY	2.98
8OIS	ELECTRON MICROSCOPY	3
9G5C	ELECTRON MICROSCOPY	3
9G5D	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P82650-F1	82.51	0.70

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 54, 211

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-5368286	Mitochondrial translation initiation
R-HSA-5389840	Mitochondrial translation elongation
R-HSA-5419276	Mitochondrial translation termination
R-HSA-9937383	Mitochondrial ribosome-associated quality control
R-HSA-392499	Metabolism of proteins
R-HSA-5368287	Mitochondrial translation
R-HSA-72766	Translation

MSigDB gene sets: 256 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOMF_STRUCTURAL_CONSTITUENT_OF_RIBOSOME, MARTIN_VIRAL_GPCR_SIGNALING_DN, GOCC_MITOCHONDRIAL_ENVELOPE, TIEN_INTESTINE_PROBIOTICS_24HR_UP, BERENJENO_TRANSFORMED_BY_RHOA_UP, MULLIGHAN_MLL_SIGNATURE_2_DN, GOCC_RIBOSOME, GOCC_SMALL_RIBOSOMAL_SUBUNIT, GOCC_ORGANELLAR_RIBOSOME, GOCC_MITOCHONDRIAL_MATRIX, GOCC_ORGANELLE_INNER_MEMBRANE

GO Biological Process (1): mitochondrial translation (GO:0032543)

GO Molecular Function (2): structural constituent of ribosome (GO:0003735), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial ribosome (GO:0005761), mitochondrial small ribosomal subunit (GO:0005763), ribosome (GO:0005840), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial translation	4
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	1
translation	1
mitochondrial gene expression	1
structural molecule activity	1
ribosome	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organellar ribosome	1
mitochondrial matrix	1
organellar small ribosomal subunit	1
mitochondrial ribosome	1
mitochondrial protein-containing complex	1
intracellular membraneless organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

2412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRPS22	MRPS16	Q9Y3D3	965
MRPS22	TSFM	P43897	895
MRPS22	TUFM	P49411	864
MRPS22	GFM1	Q96RP9	837
MRPS22	FOXL2	P58012	816
MRPS22	COPB2	P35606	790
MRPS22	HOGA1	Q86XE5	764
MRPS22	ERAL1	O75616	689
MRPS22	MRPS18B	Q9Y676	664
MRPS22	MRPL12	P52815	657
MRPS22	MRPL11	Q9Y3B7	651
MRPS22	MRPS34	P82930	645
MRPS22	MRPL45	Q9BRJ2	641
MRPS22	MRPL49	Q13405	624
MRPS22	LRPPRC	P42704	604

IntAct

195 interactions, top by confidence:

A	B	Type	Score
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ERBB3	PIK3R2	psi-mi:“MI:0914”(association)	0.700
NOP53	RRP8	psi-mi:“MI:0914”(association)	0.640
MRPS27	MRPS14	psi-mi:“MI:0914”(association)	0.640
ESR1	TRIM24	psi-mi:“MI:0914”(association)	0.640
IGF2BP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
MRPS18B	MRPS22	psi-mi:“MI:0915”(physical association)	0.560
NP	KPNA6	psi-mi:“MI:0914”(association)	0.550
RPS6	IPO7	psi-mi:“MI:0914”(association)	0.530
E4F1	ZBTB24	psi-mi:“MI:0914”(association)	0.530
MRPS15	MRPS14	psi-mi:“MI:0914”(association)	0.530
RPL6	MRPS14	psi-mi:“MI:0914”(association)	0.530
YBX1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
MRPS18B	MRPS14	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
SNRNP70	GTPBP1	psi-mi:“MI:0914”(association)	0.530
MRPS34	ZZEF1	psi-mi:“MI:0914”(association)	0.530
MRPS18C	MRPS14	psi-mi:“MI:0914”(association)	0.530
MRPS15	PRKACG	psi-mi:“MI:0914”(association)	0.530
MRPS27	YBX1	psi-mi:“MI:0914”(association)	0.530
MRPS34	MRPS12	psi-mi:“MI:0914”(association)	0.530
MRPS11	MRPS14	psi-mi:“MI:0914”(association)	0.530
MRPS17	MRPS22	psi-mi:“MI:0914”(association)	0.530
AURKAIP1	NRDC	psi-mi:“MI:0914”(association)	0.480
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430

BioGRID (378): MRPS22 (Affinity Capture-RNA), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS)

ESM2 similar proteins: A1Z9A8, A2BID5, A2VD95, A6H8H2, O70481, O75153, P41229, P41230, P70302, P82649, P82650, P84903, Q08CK1, Q0IHP3, Q0V9C9, Q0VA04, Q13586, Q14C51, Q1L987, Q1LXZ7, Q2KI62, Q32LU7, Q32N55, Q32NQ7, Q32PH0, Q32PI8, Q38JA7, Q3SX05, Q3U1Y4, Q498P2, Q4R5Q4, Q566X6, Q58CP9, Q5I0I8, Q5R8W8, Q5VZ89, Q5XIC2, Q66JD1, Q68F70, Q7Z3E5

Diamond homologs: P82649, P82650, Q9CXW2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MRPS22	“form complex”	“28S mitochondrial small ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 218 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial translation initiation	24	20.6×	7e-23
Mitochondrial translation elongation	24	20.6×	7e-23
Mitochondrial translation	22	20.4×	4e-21
Mitochondrial ribosome-associated quality control	24	19.9×	1e-22
Mitochondrial translation termination	24	17.8×	2e-21
Nuclear events stimulated by ALK signaling in cancer	5	11.0×	5e-03
Translation	26	10.9×	7e-18
Signaling by ALK fusions and activated point mutants	8	8.1×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	24	21.6×	1e-22
translation	16	8.5×	5e-08
ribosomal small subunit biogenesis	7	8.3×	4e-03
RNA splicing	12	5.5×	6e-04
mRNA processing	12	4.9×	2e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	11	4.5×	4e-03
negative regulation of apoptotic process	17	3.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

217 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	5
Uncertain significance	95
Likely benign	52
Benign	25

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1033933	NM_020191.4(MRPS22):c.874_875del (p.Asp292fs)	Pathogenic
1985689	NM_020191.4(MRPS22):c.571C>T (p.Arg191Ter)	Pathogenic
214685	NM_020191.4(MRPS22):c.768_769del (p.Gly257fs)	Pathogenic
2177068	NM_020191.4(MRPS22):c.33G>A (p.Trp11Ter)	Pathogenic
2186381	NM_020191.4(MRPS22):c.40_41insA (p.Leu14fs)	Pathogenic
2228711	NM_020191.4(MRPS22):c.373C>T (p.Arg125Ter)	Pathogenic
2691748	NM_020191.4(MRPS22):c.648+1G>T	Pathogenic
2820420	NM_020191.4(MRPS22):c.544del (p.Arg182fs)	Pathogenic
2984216	NM_020191.4(MRPS22):c.760_763del (p.Asp254fs)	Pathogenic
30524	NM_020191.4(MRPS22):c.644T>C (p.Leu215Pro)	Pathogenic
4279693	NM_020191.4(MRPS22):c.948_949del (p.Ala317fs)	Pathogenic
432184	NM_020191.4(MRPS22):c.878+1G>T	Pathogenic
521613	NM_020191.4(MRPS22):c.489T>G (p.Tyr163Ter)	Pathogenic
1806198	NM_020191.4(MRPS22):c.992_993del (p.Phe331fs)	Likely pathogenic
2445204	NM_020191.4(MRPS22):c.481dup (p.Ile161fs)	Likely pathogenic
2827805	NM_020191.4(MRPS22):c.649-2A>G	Likely pathogenic
4081519	NM_020191.4(MRPS22):c.403C>T (p.Arg135Ter)	Likely pathogenic
916071	NM_020191.4(MRPS22):c.938C>A (p.Ser313Ter)	Likely pathogenic

SpliceAI

4953 predictions. Top by Δscore:

Variant	Effect	Δscore
3:139348156:TTA:T	acceptor_loss	1.0000
3:139348157:TAGGC:T	acceptor_loss	1.0000
3:139348158:A:AC	acceptor_loss	1.0000
3:139348158:A:AG	acceptor_gain	1.0000
3:139348159:G:GG	acceptor_gain	1.0000
3:139348254:A:G	donor_gain	1.0000
3:139348265:G:GT	donor_gain	1.0000
3:139350176:TA:T	acceptor_loss	1.0000
3:139350177:A:AG	acceptor_gain	1.0000
3:139350177:AG:A	acceptor_gain	1.0000
3:139350178:G:GA	acceptor_gain	1.0000
3:139350178:GG:G	acceptor_gain	1.0000
3:139350178:GGA:G	acceptor_gain	1.0000
3:139350178:GGAGC:G	acceptor_gain	1.0000
3:139350308:G:GT	donor_gain	1.0000
3:139350319:TAGG:T	donor_loss	1.0000
3:139350320:AGG:A	donor_loss	1.0000
3:139350321:GG:G	donor_gain	1.0000
3:139350322:GG:G	donor_gain	1.0000
3:139350322:GGTA:G	donor_loss	1.0000
3:139350323:G:GG	donor_gain	1.0000
3:139350323:GTAAG:G	donor_loss	1.0000
3:139350324:T:G	donor_loss	1.0000
3:139352615:T:G	acceptor_gain	1.0000
3:139352642:GATA:G	acceptor_loss	1.0000
3:139352644:TAGGT:T	acceptor_loss	1.0000
3:139352645:AGG:A	acceptor_loss	1.0000
3:139352646:G:A	acceptor_loss	1.0000
3:139352788:GATTT:G	donor_gain	1.0000
3:139352790:TTT:T	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000374338 (3:139348117 T>C), RS1000515043 (3:139353059 C>T), RS1000515840 (3:139352847 C>A), RS1000821664 (3:139353246 A>T), RS1000903498 (3:139345320 G>C), RS1001118181 (3:139351577 C>G), RS1001170764 (3:139352975 A>C), RS1001314618 (3:139352303 T>G), RS1001402644 (3:139351843 C>T), RS1001683797 (3:139352702 G>A), RS1001725974 (3:139346225 C>T), RS1001757163 (3:139345949 C>G,T), RS1002231901 (3:139351742 G>A), RS1002509862 (3:139356961 C>G,T), RS1002669181 (3:139343608 C>T)

Disease associations

OMIM: gene MIM:605810 | disease phenotypes: MIM:611719, MIM:618117, MIM:233300, MIM:253590, MIM:609060

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotonia with lactic acidemia and hyperammonemia	Strong	Autosomal recessive
ovarian dysgenesis 7	Strong	Autosomal recessive
46 XX gonadal dysgenesis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (7): hypotonia with lactic acidemia and hyperammonemia (MONDO:0012718), ovarian dysgenesis 7 (MONDO:0020857), mitochondrial disease (MONDO:0044970), 46 XX gonadal dysgenesis (MONDO:0009299), muscular dystrophy, adult-onset, with leukoencephalopathy (MONDO:0009674), primary ovarian failure (MONDO:0005387), hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (MONDO:0012191)

Orphanet (5): Hypotonia with lactic acidemia and hyperammonemia (Orphanet:137908), Mitochondrial disease (Orphanet:68380), 46,XX gonadal dysgenesis (Orphanet:243), Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (Orphanet:137681), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000062	Ambiguous genitalia
HP:0000091	Abnormal renal tubule morphology
HP:0000133	Gonadal dysgenesis
HP:0000144	Decreased fertility
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000837	Increased circulating gonadotropin level
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0000969	Edema
HP:0001166	Arachnodactyly
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001541	Ascites
HP:0001639	Hypertrophic cardiomyopathy
HP:0001939	Abnormality of metabolism/homeostasis
HP:0001942	Metabolic acidosis
HP:0001987	Hyperammonemia

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001288_4	Obesity-related traits	5.000000e-08
GCST001288_5	Obesity-related traits	2.000000e-06
GCST001762_600	Obesity-related traits	9.000000e-06
GCST001762_649	Obesity-related traits	8.000000e-06
GCST002999_3	Lobe size	3.000000e-14
GCST003001_4	Ear morphology	2.000000e-11
GCST003983_35	Male-pattern baldness	3.000000e-09
GCST005192_117	Lobe attachment (rater-scored or self-reported)	3.000000e-49
GCST005193_18	Lobe attachment (rater scored)	5.000000e-13
GCST005193_5	Lobe attachment (rater scored)	2.000000e-18
GCST005790_90	Rosacea symptom severity	3.000000e-06
GCST008363_107	Offspring birth weight	4.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004501	HOMA-IR
EFO:0007666	lobe size
EFO:0007664	outer ear morphology trait
EFO:0007667	lobe attachment
EFO:0009180	rosacea severity measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D023961	Gonadal Dysgenesis, 46,XX	C12.050.351.875.253.064.249; C12.050.351.875.253.309.193; C12.200.706.316.064.249; C12.200.706.316.309.193; C12.800.316.064.249; C12.800.316.309.193; C16.131.939.316.064.249; C16.131.939.316.309.193; C19.391.119.064.249; C19.391.119.309.193
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C563797	Combined Oxidative Phosphorylation Deficiency 1 (supp.)
C567126	Combined Oxidative Phosphorylation Deficiency 5 (supp.)
C565361	Muscular Dystrophy, Adult-Onset, with Leukoencephalopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066461 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.99	Kd	1.029	nM	CHEMBL5653589
8.99	ED50	1.029	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148776: Binding affinity to human MRPS22 incubated for 45 mins by Kinobead based pull down assay	kd	0.0010	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
bisphenol S	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
deoxynivalenol	increases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
microcystin RR	decreases expression	1
4-phenylbutyric acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Acetaminophen	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1
Dexamethasone	increases expression, affects cotreatment	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	affects expression	1
T-2 Toxin	increases expression	1
Tunicamycin	increases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651818	Binding	Binding affinity to human MRPS22 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_XQ63	HAP1 MRPS22 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

178 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels