PTRH2

Summary

PTRH2 (peptidyl-tRNA hydrolase 2, HGNC:24265) is a protein-coding gene on chromosome 17q23.1, encoding Peptidyl-tRNA hydrolase 2, mitochondrial (Q9Y3E5). Peptidyl-tRNA hydrolase which releases tRNAs from the ribosome during protein synthesis.

The protein encoded by this gene is a mitochondrial protein with two putative domains, an N-terminal mitochondrial localization sequence, and a UPF0099 domain. In vitro assays suggest that this protein possesses peptidyl-tRNA hydrolase activity, to release the peptidyl moiety from tRNA, thereby preventing the accumulation of dissociated peptidyl-tRNA that could reduce the efficiency of translation. This protein also plays a role regulating cell survival and death. It promotes survival as part of an integrin-signaling pathway for cells attached to the extracellular matrix (ECM), but also promotes apoptosis in cells that have lost their attachment to the ECM, a process called anoikos. After loss of cell attachment to the ECM, this protein is phosphorylated, is released from the mitochondria into the cytosol, and promotes caspase-independent apoptosis through interactions with transcriptional regulators. This gene has been implicated in the development and progression of tumors, and mutations in this gene have been associated with an infantile multisystem neurologic, endocrine, and pancreatic disease (INMEPD) characterized by intellectual disability, postnatal microcephaly, progressive cerebellar atrophy, hearing impairment, polyneuropathy, failure to thrive, and organ fibrosis with exocrine pancreas insufficiency (PMID: 25574476). Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 51651 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 51 total — 1 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 69
• MANE Select transcript: NM_016077

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24265
Approved symbol	PTRH2
Name	peptidyl-tRNA hydrolase 2
Location	17q23.1
Locus type	gene with protein product
Status	Approved
Aliases	BIT1, CGI-147, PTH2, CFAP37
Ensembl gene	ENSG00000141378
Ensembl biotype	protein_coding
OMIM	608625
Entrez	51651

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 19 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000393038, ENST00000409433, ENST00000470557, ENST00000579915, ENST00000587935, ENST00000892066, ENST00000892067, ENST00000892068, ENST00000892069, ENST00000892070, ENST00000892071, ENST00000892072, ENST00000913128, ENST00000913129, ENST00000913130, ENST00000913131, ENST00000913132, ENST00000913133, ENST00000913134, ENST00000913135, ENST00000961197

RefSeq mRNA: 2 — MANE Select: NM_016077 NM_001015509, NM_016077

CCDS: CCDS11618, CCDS77076

Canonical transcript exons

ENST00000393038 — 2 exons

Exon	Start	End
ENSE00001514035	59707371	59707430
ENSE00003902850	59697308	59697978

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 95.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.4720 / max 391.7811, expressed in 1814 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167336	32.4720	1814

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	95.35	gold quality
islet of Langerhans	UBERON:0000006	95.03	gold quality
endothelial cell	CL:0000115	93.89	gold quality
mucosa of transverse colon	UBERON:0004991	93.26	gold quality
tendon of biceps brachii	UBERON:0008188	92.61	gold quality
tongue squamous epithelium	UBERON:0006919	92.20	gold quality
middle temporal gyrus	UBERON:0002771	92.02	gold quality
stromal cell of endometrium	CL:0002255	91.37	gold quality
gingival epithelium	UBERON:0001949	91.13	gold quality
cartilage tissue	UBERON:0002418	91.02	gold quality
rectum	UBERON:0001052	90.90	gold quality
left adrenal gland	UBERON:0001234	90.75	gold quality
pancreas	UBERON:0001264	90.72	gold quality
right adrenal gland	UBERON:0001233	90.64	gold quality
right adrenal gland cortex	UBERON:0035827	90.61	gold quality
left adrenal gland cortex	UBERON:0035825	90.60	gold quality
cervix epithelium	UBERON:0004801	90.36	gold quality
adrenal cortex	UBERON:0001235	90.14	gold quality
adrenal gland	UBERON:0002369	90.12	gold quality
monocyte	CL:0000576	90.03	gold quality
hair follicle	UBERON:0002073	89.96	gold quality
mononuclear cell	CL:0000842	89.90	gold quality
leukocyte	CL:0000738	89.88	gold quality
body of pancreas	UBERON:0001150	89.79	gold quality
right lobe of liver	UBERON:0001114	89.44	gold quality
gastrocnemius	UBERON:0001388	89.36	gold quality
granulocyte	CL:0000094	89.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.29	gold quality
prefrontal cortex	UBERON:0000451	89.18	gold quality
epithelial cell of pancreas	CL:0000083	89.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.87

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BCL2	Repression

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

9 targeting PTRH2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-4259	95.68	65.25	582

Literature-anchored findings (GeneRIF, showing 23)

• Results identify Bit1, a mitochondrial protein released into the cytoplasm during apoptosis that forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein (PMID:15006356)
• Reduced expression of the proapoptotic proteins Bit1 or overexpression of Bcl-2 improved myoblast transplantation survival. (PMID:17511679)
• the PKD serine/threonine kinase is one of the signaling molecules through which integrin-mediated cell attachment controls Bit1 activity and anoikis (PMID:18703509)
• TAp63gamma could induce apoptosis in human esophageal squamous cancer EC9706 cells, through at least releasing AIF and Bit1 from mitochindria into cytosol and nucleus, where apoptotic cascade takes place. (PMID:19578750)
• Bit-1 mediates integrin-dependent cell survival through activation of the NFkappaB pathway (PMID:21383007)
• downregulation of Bit1 conferred cancer cells with enhanced anoikis resistance, adhesive and migratory properties in vitro (PMID:21886829)
• TLE1 inhibits the Bit1 anoikis pathway by reducing the formation of the proapoptotic Bit1-AES complex in part through sequestration of AES in the nucleus. (PMID:22952044)
• Data indicate that the cell death domain (CDD) to the N-terminal 62 amino acids of Bit1 was more potent in killing cells than the full-length Bit1 protein when equivalent amounts of cDNA were transfected. (PMID:23248118)
• Bit1 may be a useful pathological marker and a prognostic marker for serous papillary adenocarcinomas outcome. (PMID:23259782)
• Bit1 plays pivotal roles in the development and progression of ESCC, and its biological functions in ESCC may be closely associated with AIF and Bcl-2 levels. (PMID:23955799)
• these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. (PMID:25003198)
• Reduction of the Bit1 level in cytosol, regulated by E2 binding to ESR1, was mainly mediated through PI3K/AKT pathways. (PMID:25211327)
• Bit1 may be an important regulator in cell growth, apoptosis, migration and invasion of esophageal squamous cell carcinoma via targeting FAK-paxillin pathway. (PMID:26956728)
• This study reports on five infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. (PMID:27129381)
• studies indicate Bit1 is an inhibitor of EMT and metastasis in lung cancer and hence can serve as a molecular target in curbing lung cancer aggressiveness (PMID:27655370)
• Our data establishes a PTRH2 mutation as a novel driver of congenital muscle degeneration and identifies a potential novel target to treat muscle myopathies. (PMID:28175314)
• Homozygous mutation in PTRH2 gene causes progressive sensorineural deafness and peripheral neuropathy in three sisters from a consanguineous family. (PMID:28328138)
• Bcl-2 expression patterns in various differentiated esophageal squamous cell carcinoma were higher than those in corresponding normal esophageal tissues with no statistical differences ( p > 0.05). Importantly, Bit1 expression was positively correlated with both matrix metalloproteinase 2 and Bcl-2 expression in esophageal squamous cell carcinoma and esophageal adenocarcinoma tissues ( p < 0.05). (PMID:28488526)
• These collective findings indicate that loss of Bit1 expression contributes to the acquisition of malignant phenotype of human lung epithelial cells via Erk activation-induced suppression of E-cadherin expression. (PMID:29170133)
• We report three brothers born to consanguineous parents of Syrian descent, with a homozygous novel c.324G>A (p.W108*) mutation in PTRH2 that encodes peptidyl-tRNA hydrolase 2, causing infantile-onset multisystem neurologic, endocrine, and pancreatic disease (PMID:31057140)
• Bit1 may serve as a novel regulator of astrocyte biological behaviors interplaying with vascular endothelial cell during retinal development. (PMID:31368047)
• Bit1 is involved in regulation between integrin and TGFbeta signaling in lens epithelial cells. (PMID:35737738)
• PTRH2 Gene Variants: Recent Review of the Phenotypic Features and Their Bioinformatics Analysis. (PMID:37239392)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptrh2	ENSDARG00000077339
mus_musculus	Ptrh2	ENSMUSG00000072582
rattus_norvegicus	Ptrh2	ENSRNOG00000076410
drosophila_melanogaster	CG1307	FBGN0026566
drosophila_melanogaster	CG17327	FBGN0038107

Protein

Protein identifiers

Peptidyl-tRNA hydrolase 2, mitochondrial — Q9Y3E5 (reviewed: Q9Y3E5)

Alternative names: Bcl-2 inhibitor of transcription 1

All UniProt accessions (2): Q9Y3E5, J3KQ48

UniProt curated annotations — full annotation on UniProt →

Function. Peptidyl-tRNA hydrolase which releases tRNAs from the ribosome during protein synthesis. Promotes caspase-independent apoptosis by regulating the function of two transcriptional regulators, AES and TLE1.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion outer membrane.

Post-translational modifications. Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.

Disease relevance. Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1 (IMNEPD1) [MIM:616263] A progressive multisystem disease characterized by a variety of neurologic, endocrine, and, in some patients, pancreatic features. Variable clinical symptoms include global developmental delay, hypotonia, hearing loss, ataxia, hyporeflexia, facial dysmorphism, hypothyroidism, and pancreatic insufficiency. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the PTH2 family.

RefSeq proteins (2): NP_001015509, NP_057161* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002833	PTH2	Family
IPR023476	Pep_tRNA_hydro_II_dom_sf	Homologous_superfamily

Pfam: PF01981

Enzyme classification (BRENDA):

• EC 3.1.1.29 — peptidyl-tRNA hydrolase (BRENDA: 24 organisms, 89 substrates, 19 inhibitors, 50 Km, 45 kcat entries)

Substrate kinetics (BRENDA)

22 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DIACETYL-LYSYL-TRNALYS	—	14
DIACETYL-LYS-TRNALYS	—	9
DIACETYL-LYSINE-TRNA	—	5
N-ACETYL-ALA-TRNA(ALA)	0.0047–0.0269	4
FORMYL-METHIONYL-TRNAFMET	—	2
ACETYL-HIS-TRNAHIS	—	1
ACETYL-HISTIDYL-TRNA	—	1
ACETYL-HISTIDYL-TRNAHIS	—	1
BULK PEPTIDYL-TRNA	0.008	1
DEPHOSPHORYLATED DIACYL-LYSINE-TRNA	—	1
DEPHOSPHORYLATED FORMYL-MET-TRNAFMET	—	1
DEPHOSPHORYLATED FORMYL-METHIONINYL-TRNA	—	1
FORMYL-MET-TRNAFMET	—	1
FORMYL-METHIONYL-TRNA	—	1
N-ACETYL-MET-TRNA	0.0022	1

Catalyzed reactions (Rhea), 1 shown:

• an N-acyl-L-alpha-aminoacyl-tRNA + H2O = an N-acyl-L-amino acid + a tRNA + H(+) (RHEA:54448)

UniProt features (21 total): cross-link 8, strand 5, helix 5, chain 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1Q7S	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3E5-F1	84.10	0.61

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 (8): 47, 76, 81, 95, 106, 115, 171, 177

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 328 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, BENPORATH_ES_WITH_H3K27ME3, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, ONKEN_UVEAL_MELANOMA_UP, TCF11_01, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_NEGATIVE_REGULATION_OF_ANOIKIS, MARZEC_IL2_SIGNALING_UP, LAU_APOPTOSIS_CDKN2A_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_REGULATION_OF_ANOIKIS, MARCINIAK_ER_STRESS_RESPONSE_VIA_CHOP

GO Biological Process (4): apoptotic process (GO:0006915), negative regulation of gene expression (GO:0010629), positive regulation of anoikis (GO:2000210), negative regulation of anoikis (GO:2000811)

GO Molecular Function (3): peptidyl-tRNA hydrolase activity (GO:0004045), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anoikis	2
regulation of anoikis	2
cytoplasm	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
positive regulation of apoptotic process	1
negative regulation of apoptotic process	1
carboxylic ester hydrolase activity	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1

Protein interactions and networks

STRING

1512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTRH2	TLE5	Q08117	791
PTRH2	BCL2	P10415	527
PTRH2	UBQLN1	Q9UMX0	502
PTRH2	UBQLN2	Q9UHD9	490
PTRH2	FN1	P02751	483
PTRH2	TLE1	Q04724	475
PTRH2	BTBD8	Q5XKL5	459
PTRH2	PTRH1	Q86Y79	455
PTRH2	APPBP2	Q92624	447
PTRH2	TUBD1	Q9UJT1	447
PTRH2	TRAPPC6B	Q86SZ2	444
PTRH2	MRPL44	Q9H9J2	434
PTRH2	CHCT1	Q86WR6	430
PTRH2	MAPK1	P28482	425
PTRH2	RNFT1	Q5M7Z0	423

IntAct

129 interactions, top by confidence:

A	B	Type	Score
TLE5	PTRH2	psi-mi:“MI:0915”(physical association)	0.690
PTRH2	TLE5	psi-mi:“MI:0915”(physical association)	0.690
ETFRF1	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
CD7	PTRH2	psi-mi:“MI:0915”(physical association)	0.620
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
TEX29	TOR1A	psi-mi:“MI:0914”(association)	0.530
CLEC5A	TSPAN6	psi-mi:“MI:0914”(association)	0.530
TLR5	MAN1A2	psi-mi:“MI:0914”(association)	0.530
HMOX2	PRAF2	psi-mi:“MI:0914”(association)	0.530
PHYHIP	TRIP6	psi-mi:“MI:0914”(association)	0.530
CD7	MYADM	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CHRM3	PLD2	psi-mi:“MI:0914”(association)	0.530
VAMP5	NBAS	psi-mi:“MI:0914”(association)	0.530
TNFRSF10B	FADD	psi-mi:“MI:0914”(association)	0.530
EVA1B	NRP1	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	TK2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (292): PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), AES (Two-hybrid), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS)

ESM2 similar proteins: A4FUF0, A4Q9F4, B0K012, E9PTA2, O15315, O35719, O43502, O54804, O54929, O94759, P0C0T1, P42694, Q0V8J1, Q0VGM9, Q3U2J5, Q3ZBL5, Q49A26, Q5BIM1, Q5R7T2, Q5RJZ1, Q5RKH0, Q5ZIA0, Q5ZLS7, Q6DC64, Q6DFV5, Q6IE70, Q6NYU2, Q6P4H8, Q7Z624, Q80VL1, Q86W50, Q8BYN3, Q8CIW5, Q8NHH1, Q8R1C6, Q8R1G1, Q8R2J9, Q8R2Y8, Q91YD4, Q922P9

Diamond homologs: A3DMF7, A4FYL9, A4YD82, A6USA3, A6UWF5, A6VJR3, A8MBW8, A9A6B6, B0R2Y5, B6YTE3, B9LTP1, C3MJ30, C3MYS2, C3MZS7, C3N851, C3NF60, C4KJ09, C6A1K8, O13830, O27732, O28185, O74017, O76387, O97067, P34222, P61234, P61235, P61414, Q12WH8, Q18KN8, Q3ZBL5, Q466V4, Q54ZD0, Q5JDB8, Q5V1D3, Q60363, Q877G5, Q8Q0M4, Q8R2Y8, Q8TKX4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKD1	up-regulates	PTRH2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	6
Uncertain significance	24
Likely benign	14
Benign	1

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
183332	NM_016077.5(PTRH2):c.254A>C (p.Gln85Pro)	Pathogenic
1048079	NM_016077.5(PTRH2):c.127dup (p.Ser43fs)	Likely pathogenic
3896966	NM_016077.5(PTRH2):c.92G>A (p.Trp31Ter)	Likely pathogenic
451081	NM_016077.5(PTRH2):c.253C>T (p.Gln85Ter)	Likely pathogenic
4814177	NM_016077.5(PTRH2):c.100C>T (p.Arg34Ter)	Likely pathogenic
524094	NM_016077.5(PTRH2):c.111dup (p.Gly38fs)	Likely pathogenic
996539	NM_016077.5(PTRH2):c.68T>C (p.Val23Ala)	Likely pathogenic

SpliceAI

2211 predictions. Top by Δscore:

Variant	Effect	Δscore
17:59674693:A:AG	acceptor_gain	1.0000
17:59674694:A:G	acceptor_gain	1.0000
17:59674698:CAGG:C	acceptor_loss	1.0000
17:59674699:A:AC	acceptor_loss	1.0000
17:59674699:A:AG	acceptor_gain	1.0000
17:59674700:G:A	acceptor_loss	1.0000
17:59674700:G:GA	acceptor_gain	1.0000
17:59674785:GTT:G	donor_gain	1.0000
17:59674864:GGA:G	donor_gain	1.0000
17:59674865:GA:G	donor_gain	1.0000
17:59674866:A:G	donor_gain	1.0000
17:59676950:CTAGA:C	acceptor_loss	1.0000
17:59676951:TAG:T	acceptor_loss	1.0000
17:59676952:A:AG	acceptor_gain	1.0000
17:59676952:A:T	acceptor_loss	1.0000
17:59676953:G:GA	acceptor_loss	1.0000
17:59676953:G:GG	acceptor_gain	1.0000
17:59676953:GATT:G	acceptor_gain	1.0000
17:59677184:TTAAT:T	donor_gain	1.0000
17:59677185:TAAT:T	donor_gain	1.0000
17:59677186:AAT:A	donor_gain	1.0000
17:59677187:AT:A	donor_gain	1.0000
17:59677187:ATG:A	donor_loss	1.0000
17:59677188:TG:T	donor_loss	1.0000
17:59677189:G:GG	donor_gain	1.0000
17:59677189:GTG:G	donor_loss	1.0000
17:59677190:TGAG:T	donor_loss	1.0000
17:59679392:TTTA:T	acceptor_loss	1.0000
17:59679393:TTAG:T	acceptor_loss	1.0000
17:59679394:TAGGT:T	acceptor_loss	1.0000

AlphaMissense

1159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:59697655:C:A	W108C	0.996
17:59697655:C:G	W108C	0.996
17:59697657:A:G	W108R	0.995
17:59697657:A:T	W108R	0.995
17:59697721:G:C	C86W	0.995
17:59697544:A:C	D145E	0.994
17:59697544:A:T	D145E	0.994
17:59697634:C:A	K115N	0.994
17:59697634:C:G	K115N	0.994
17:59697723:A:G	C86R	0.994
17:59697536:C:G	R148P	0.993
17:59697545:T:G	D145A	0.993
17:59697711:C:G	A90P	0.993
17:59697736:T:A	K81N	0.993
17:59697736:T:G	K81N	0.993
17:59697737:T:A	K81I	0.993
17:59697494:C:T	G162E	0.992
17:59697546:C:G	D145H	0.992
17:59697710:G:T	A90D	0.992
17:59697506:A:T	V158D	0.991
17:59697731:G:T	A83D	0.991
17:59697767:A:T	V71D	0.991
17:59697545:T:C	D145G	0.990
17:59697713:G:T	A89D	0.990
17:59697728:G:T	A84D	0.990
17:59697503:A:G	L159P	0.989
17:59697545:T:A	D145V	0.989
17:59697717:G:C	H88D	0.989
17:59697566:A:G	L138P	0.988
17:59697707:A:T	V91D	0.988

dbSNP variants (sampled 300 via entrez): RS1000402798 (17:59705096 T>A,G), RS1000421433 (17:59698814 T>G), RS1000626254 (17:59699080 T>A,C), RS1000801945 (17:59707006 C>A), RS1000851353 (17:59708057 C>T), RS1001232841 (17:59697583 A>T), RS1001390437 (17:59699127 A>G), RS1001515976 (17:59705076 C>A,G), RS1001555450 (17:59705562 G>A,C), RS1001829587 (17:59697121 G>C), RS1003176604 (17:59708375 G>A,C), RS1003651397 (17:59703807 A>C), RS1003753038 (17:59702313 C>T), RS1003802420 (17:59702513 C>T), RS1003935731 (17:59705924 A>C)

Disease associations

OMIM: gene MIM:608625 | disease phenotypes: MIM:616263

GenCC curated gene-disease

Disease	Classification	Inheritance
neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1	Definitive	Autosomal recessive
infantile multisystem neurologic-endocrine-pancreatic disease	Supportive	Autosomal recessive

Mondo (5): neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1 (MONDO:8000012), cerebellar ataxia (MONDO:0000437), hearing loss disorder (MONDO:0005365), neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset (MONDO:0024189), (MONDO:0014554)

Orphanet (2): Infantile multisystem neurologic-endocrine-pancreatic disease (Orphanet:456312), Rare ataxia (Orphanet:102002)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000049	Shawl scrotum
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000253	Progressive microcephaly
HP:0000309	Abnormal midface morphology
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000577	Exotropia
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0001155	Abnormality of the hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001319	Neonatal hypotonia
HP:0001374	Congenital hip dislocation
HP:0001395	Hepatic fibrosis
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001530	Mild postnatal growth retardation
HP:0001558	Decreased fetal movement
HP:0001738	Exocrine pancreatic insufficiency

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Estradiol	increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	affects expression	1
sodium arsenate	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
ochratoxin A	decreases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
motexafin gadolinium	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Benzoates	decreases expression	1
Cadmium	increases abundance, increases palmitoylation, decreases reaction	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3FD	Abcam HEK293T PTRH2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer