PITRM1

Summary

PITRM1 (pitrilysin metallopeptidase 1, HGNC:17663) is a protein-coding gene on chromosome 10p15.2, encoding Presequence protease, mitochondrial (Q5JRX3). Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing. It is a selective cancer dependency (DepMap: 24.7% of cell lines).

The protein encoded by this gene is an ATP-dependent metalloprotease that degrades post-cleavage mitochondrial transit peptides. The encoded protein binds zinc and can also degrade amyloid beta A4 protein, suggesting a possible role in Alzheimer’s disease.

Source: NCBI Gene 10531 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive 30 (Strong, GenCC)
• GWAS associations: 33
• Clinical variants (ClinVar): 571 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 24.7% of screened cell lines
• MANE Select transcript: NM_014889

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17663
Approved symbol	PITRM1
Name	pitrilysin metallopeptidase 1
Location	10p15.2
Locus type	gene with protein product
Status	Approved
Aliases	MP1, KIAA1104, hMP1, PreP
Ensembl gene	ENSG00000107959
Ensembl biotype	protein_coding
OMIM	618211
Entrez	10531

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 20 protein_coding, 12 nonsense_mediated_decay, 9 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000224949, ENST00000380989, ENST00000380994, ENST00000424714, ENST00000430362, ENST00000451104, ENST00000451454, ENST00000455371, ENST00000464395, ENST00000488065, ENST00000490510, ENST00000676519, ENST00000676719, ENST00000676917, ENST00000676953, ENST00000677001, ENST00000677181, ENST00000677305, ENST00000677384, ENST00000677598, ENST00000677817, ENST00000677922, ENST00000678050, ENST00000678370, ENST00000678403, ENST00000678436, ENST00000678441, ENST00000678457, ENST00000678539, ENST00000678601, ENST00000678663, ENST00000678756, ENST00000678811, ENST00000678855, ENST00000678972, ENST00000678986, ENST00000678987, ENST00000679134, ENST00000679210, ENST00000679309, ENST00000851395, ENST00000960311, ENST00000960312, ENST00000960313, ENST00000960314

RefSeq mRNA: 9 — MANE Select: NM_014889 NM_001242307, NM_001242309, NM_001347725, NM_001347726, NM_001347727, NM_001347728, NM_001347729, NM_001347730, NM_014889

CCDS: CCDS55699, CCDS55700, CCDS59208, CCDS91205, CCDS91206

Canonical transcript exons

ENST00000224949 — 27 exons

Exon	Start	End
ENSE00000984761	3143389	3143501
ENSE00000998606	3172717	3172782
ENSE00001593991	3151247	3151363
ENSE00001598952	3147572	3147737
ENSE00001615649	3155591	3155729
ENSE00001621701	3170104	3170206
ENSE00001625569	3165413	3165527
ENSE00001651129	3148171	3148291
ENSE00001673277	3160204	3160330
ENSE00001693858	3158914	3159042
ENSE00001693880	3163725	3163885
ENSE00001702624	3166936	3167042
ENSE00001705228	3159848	3159936
ENSE00001778488	3157435	3157531
ENSE00001783986	3158040	3158153
ENSE00001785150	3166229	3166380
ENSE00001793832	3147987	3148063
ENSE00001799967	3149621	3149753
ENSE00001805897	3156930	3157064
ENSE00003492360	3165238	3165334
ENSE00003527488	3147150	3147250
ENSE00003568114	3138235	3138337
ENSE00003572696	3138904	3139049
ENSE00003609663	3144292	3144366
ENSE00003639796	3140687	3140812
ENSE00003691799	3145596	3145716
ENSE00003843068	3137728	3138124

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.5138 / max 416.8422, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107929	58.9595	1823
107928	0.6390	250
107925	0.5026	252
107926	0.4126	116

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.59	gold quality
adrenal tissue	UBERON:0018303	97.39	gold quality
right adrenal gland cortex	UBERON:0035827	96.90	gold quality
right adrenal gland	UBERON:0001233	96.79	gold quality
adenohypophysis	UBERON:0002196	96.67	gold quality
left adrenal gland	UBERON:0001234	96.53	gold quality
left testis	UBERON:0004533	96.53	gold quality
left adrenal gland cortex	UBERON:0035825	96.48	gold quality
right frontal lobe	UBERON:0002810	96.46	gold quality
descending thoracic aorta	UBERON:0002345	96.39	gold quality
right testis	UBERON:0004534	96.35	gold quality
left ovary	UBERON:0002119	96.32	gold quality
ascending aorta	UBERON:0001496	96.28	gold quality
thoracic aorta	UBERON:0001515	96.25	gold quality
popliteal artery	UBERON:0002250	96.14	gold quality
tibial artery	UBERON:0007610	96.14	gold quality
aorta	UBERON:0000947	96.13	gold quality
right ovary	UBERON:0002118	96.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.10	gold quality
lower esophagus	UBERON:0013473	96.09	gold quality
islet of Langerhans	UBERON:0000006	96.01	gold quality
gastrocnemius	UBERON:0001388	95.93	gold quality
metanephros cortex	UBERON:0010533	95.90	gold quality
left lobe of thyroid gland	UBERON:0001120	95.86	gold quality
adrenal gland	UBERON:0002369	95.84	gold quality
left coronary artery	UBERON:0001626	95.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.79	gold quality
right coronary artery	UBERON:0001625	95.74	gold quality
adrenal cortex	UBERON:0001235	95.73	gold quality
cerebellar hemisphere	UBERON:0002245	95.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.31
E-MTAB-7606	no	251.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

15 targeting PITRM1, 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-4682	100.00	68.89	1258
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-4712-5P	97.24	67.79	775
HSA-MIR-770-5P	97.24	68.10	758
HSA-MIR-4662A-3P	97.02	67.77	941
HSA-MIR-668-3P	96.18	65.80	673

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• The substrate specificity of the mitochondrial metallopeptidase proteinase 1 (MP1) was investigated and its mitochondrial targeting signal identified. (PMID:19196155)
• Data revealed that six polymorphisms of F10, PITRM1, PCSK2, JPH3, MYO7B, and AKAP12 were related (P<0.05) to the prevalence of chronic kidney disease. (PMID:19724895)
• our data suggest that genetic variation in the hPreP gene PITRM1 may potentially contribute to mitochondrial dysfunctions (PMID:19962426)
• Data show that the hPreP presequence only targets GFP to the matrix of mammalian and yeast mitochondria. (PMID:21621546)
• This study demonstrated decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer’s disease brain mitochondria. (PMID:21750375)
• Redox control of hPreP in the mitochondrial matrix and the protective role of the conserved methionine 206 residue as an internal antioxidant. (PMID:23041349)
• The authors identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. (PMID:26697887)
• Single nucleotide polymorphism in PITRM1 gene is associated with smoking in African americans. (PMID:29216386)
• Mutational disruption of electrostatic interactions in proximity of Pitrm1 arginine 183 residue contributes to the loss of enzyme activity.The arginine-to-glutamine substitution mutant Pitrm1 R183Q has been implicated in inherited amyloidogenic neuropathy. (PMID:29383861)
• PITRM1 T931M mutation results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity. (PMID:29764912)
• Functional coupling of presequence processing and degradation in human mitochondria. (PMID:32491259)
• Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids. (PMID:32632204)
• Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation. (PMID:32857715)
• Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer’s disease. (PMID:33951271)
• PITRM1 interaction studies with amyloidogenic nonapeptide mutants of familial Alzheimer’s disease. (PMID:35751131)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pitrm1	ENSDARG00000038563
mus_musculus	Pitrm1	ENSMUSG00000021193
rattus_norvegicus	Pitrm1	ENSRNOG00000016511
drosophila_melanogaster	CG3107	FBGN0033005

Paralogs (6): UQCRC1 (ENSG00000010256), NRDC (ENSG00000078618), PMPCB (ENSG00000105819), IDE (ENSG00000119912), UQCRC2 (ENSG00000140740), PMPCA (ENSG00000165688)

Protein

Protein identifiers

Presequence protease, mitochondrial — Q5JRX3 (reviewed: Q5JRX3)

Alternative names: Pitrilysin metalloproteinase 1

All UniProt accessions (21): Q5JRX3, A0A0A0MRX9, A0A7I2V2T0, A0A7I2V397, A0A7I2V3B6, A0A7I2V3L7, A0A7I2V3X0, A0A7I2V449, A0A7I2V4N3, A0A7I2V4X7, A0A7I2V5C6, A0A7I2V5H2, A0A7I2V5K2, A0A7I2V5R2, A0A7I2YQT2, A0A7I2YQX5, B1APQ0, B1APQ1, B4DEU0, H0Y4F7, H0Y7L7

UniProt curated annotations — full annotation on UniProt →

Function. Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing. Has an ATP-independent activity. Specifically cleaves peptides in the range of 5 to 65 residues. Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference. Degrades the transit peptides of mitochondrial proteins after their cleavage. Also degrades other unstructured peptides. It is also able to degrade amyloid-beta protein 40, one of the peptides produced by APP processing, when it accumulates in mitochondrion. It is a highly efficient protease, at least toward amyloid-beta protein 40. Cleaves that peptide at a specific position and is probably not processive, releasing digested peptides intermediates that can be further cleaved subsequently. It is also able to degrade amyloid-beta protein 42.

Subunit / interactions. Monomer and homodimer; homodimerization is induced by binding of the substrate.

Subcellular location. Mitochondrion. Mitochondrion matrix.

Tissue specificity. Widely expressed. Expressed at higher level in muscle and heart compared to brain, pancreas, liver, lung and placenta.

Post-translational modifications. A disulfide bond locks the enzyme in the closed conformation preventing substrate entry into the catalytic chamber.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 30 (SCAR30) [MIM:619405] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR30 is a progressive disease characterized by childhood-onset global developmental delay with variably impaired intellectual development, motor dysfunction, and cerebellar ataxia. Affected individuals may also have psychiatric abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Mainly exists in a closed and catalytically competent conformation but a closed-to-open switch allows substrate entry into the catalytic chamber. Substrate binding induces closure and dimerization. A disulfide bond may lock the enzyme in a closed conformation preventing substrate entry into the catalytic chamber, participating in redox regulation of the enzyme. Inhibited by metal-chelating agents. Inhibited by nickel and zinc excess, and slightly activated by manganese.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M16 family. PreP subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5JRX3-1	1	yes
Q5JRX3-2	2
Q5JRX3-3	3

RefSeq proteins (9): NP_001229236, NP_001229238, NP_001334654, NP_001334655, NP_001334656, NP_001334657, NP_001334658, NP_001334659, NP_055704* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007863	Peptidase_M16_C	Domain
IPR011249	Metalloenz_LuxS/M16	Homologous_superfamily
IPR011765	Pept_M16_N	Domain
IPR013578	Peptidase_M16C_assoc	Domain
IPR055130	PreP_C	Domain

Pfam: PF00675, PF05193, PF08367, PF22516

Enzyme classification (BRENDA):

• EC 3.4.24.56 — insulysin (BRENDA: 12 organisms, 277 substrates, 293 inhibitors, 87 Km, 99 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ABZ-GGFLRKHGQ-EDDNP	0.0066–21.3	25
INSULIN	—	15
2-AMINOBENZOYL-GGFLRKHGQ-(N-(2,4-DINITROPHENYL)E	0.014–0.204	7
ABZ-GGFLRKHGQEDDNP	0.0059–0.0254	3
(7-METHOXYCOUMARIN-4-YL)ACETYL-KLVFFAEDK(DNP)-OH	0.0056–0.0076	2
7-METHOXYCOUMARIN-4-YL-ACETYL-RPPGFSAFK-2,4-DINI	0.0047–0.0049	2
AMYLOID BETA-PEPTIDE1-40	0.025–0.027	2
AMYLOID BETA-PROTEIN	0.0012–0.0025	2
DABCYL-TYR-GLU-VAL-HIS-HIS-GLN-LYS-LEU-VAL-PHE-P	1.2–2.3	2
PROINSULIN	0.0002–0.0009	2
(7-METHOXYCOUMARIN-4-YL)ACETYL-RPPGFSAFK(2,4-DIN	0.0099	1
ABZ-GLY-GLY-LEU-ARG-LYS-HIS-GLY-GLN-EDDNP	0.0111	1
ABZ-SEKKDNYIIKGV-NITROY-OH	0.219	1
AMYLOID BETA	0.08	1
AMYLOID BETA-PEPTIDE 1-40	0.0028	1

UniProt features (161 total): helix 59, strand 36, sequence variant 15, turn 13, mutagenesis site 13, modified residue 6, sequence conflict 6, splice variant 3, binding site 3, active site 2, transit peptide 1, chain 1, disulfide bond 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
4L3T	X-RAY DIFFRACTION	2.03
4RPU	X-RAY DIFFRACTION	2.27
4NGE	X-RAY DIFFRACTION	2.7
6XOV	ELECTRON MICROSCOPY	3.3
6XOS	ELECTRON MICROSCOPY	3.7
6XOT	ELECTRON MICROSCOPY	3.9
6XOU	ELECTRON MICROSCOPY	4
6XOW	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JRX3-F1	94.44	0.93

Functional residue map

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

Catalytic / active sites (2): 107 (proton acceptor); 180

Ligand- & substrate-binding residues (3): 104; 108; 205

Post-translational modifications (6): 770, 770, 849, 884, 946, 759

Disulfide bonds (1): 119–556

Mutagenesis-validated functional residues (13):

Position	Phenotype
1–15	loss of localization to the mitochondrion.
107	loss of metalloendopeptidase activity. loss of activity towards an amyloid-beta peptide derivative.
119	no loss of metalloendopeptidase activity under oxidizing conditions.
182–199	loss of metalloendopeptidase activity towards an amyloid-beta peptide derivative.
183	decreased metalloendopeptidase activity towards an amyloid-beta peptide derivative.
183	loss of metalloendopeptidase activity towards an amyloid-beta peptide derivative.
185	loss of metalloendopeptidase activity towards an amyloid-beta peptide derivative.
185	no effect on metalloendopeptidase activity towards an amyloid-beta peptide derivative.
185	decreased metalloendopeptidase activity towards an amyloid-beta peptide derivative.
199	decreased metalloendopeptidase activity towards an amyloid-beta peptide derivative.
199	no effect on metalloendopeptidase activity towards an amyloid-beta peptide derivative.
557	decreased metalloendopeptidase activity without effect on protein stability.
558	decreased metalloendopeptidase activity without effect on protein stability.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import

MSigDB gene sets: 298 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GCM_GSPT1, GOMF_METALLOPEPTIDASE_ACTIVITY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_REGULATION_OF_HORMONE_LEVELS, MORF_HDAC2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_MATURATION

GO Biological Process (3): proteolysis (GO:0006508), obsolete protein targeting to mitochondrion (GO:0006626), protein processing (GO:0016485)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), enzyme activator activity (GO:0008047), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	2
protein metabolic process	1
proteolysis	1
protein maturation	1
endopeptidase activity	1
metallopeptidase activity	1
enzyme regulator activity	1
molecular function activator activity	1
peptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PITRM1	F2R	P25116	871
PITRM1	MMP1	P03956	801
PITRM1	PROCR	Q9UNN8	771
PITRM1	F2RL1	P55085	724
PITRM1	S1PR3	Q99500	669
PITRM1	IDE	P14735	640
PITRM1	TIMP1	P01033	621
PITRM1	CCL2	P13500	523
PITRM1	NLN	Q9BYT8	506
PITRM1	ADAM2	P78326	486
PITRM1	MIPEP	Q99797	474
PITRM1	NDUFV2	P19404	466
PITRM1	ERMP1	Q7Z2K6	462
PITRM1	NRDC	O43847	457
PITRM1	EPRS1	P07814	442

IntAct

101 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
	PMPCB	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
CILK1	FKBP5	psi-mi:“MI:0914”(association)	0.620
	PMPCB	psi-mi:“MI:0914”(association)	0.530
PRKCSH	AURKA	psi-mi:“MI:0914”(association)	0.530
SPINK2	STRN	psi-mi:“MI:0914”(association)	0.530
CCL22	PLXNA2	psi-mi:“MI:0914”(association)	0.530
TEKT3	CLUH	psi-mi:“MI:0914”(association)	0.530
REG4	ATE1	psi-mi:“MI:0914”(association)	0.530
SPATA24	GGPS1	psi-mi:“MI:0914”(association)	0.530
PLEKHG6	CST4	psi-mi:“MI:0914”(association)	0.530
DEFB104A	IFI30	psi-mi:“MI:0914”(association)	0.530
FBXL19	MED19	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
PCARE	ARPC3	psi-mi:“MI:0914”(association)	0.510
PITRM1		psi-mi:“MI:0915”(physical association)	0.490
APP	PITRM1	psi-mi:“MI:0570”(protein cleavage)	0.440
PITRM1	INS	psi-mi:“MI:0570”(protein cleavage)	0.440
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
PAX4	PITRM1	psi-mi:“MI:0915”(physical association)	0.400
CA5A	PITRM1	psi-mi:“MI:0915”(physical association)	0.400
PITRM1	rep	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350

BioGRID (197): PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Co-fractionation), PITRM1 (Co-fractionation), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS)

ESM2 similar proteins: B0WSW8, F4HNU6, F4HTQ1, F4IDQ6, F4INY4, F4J3D9, O14077, O22941, O42908, P0DI12, P0DI13, P14735, P22817, P32898, P35559, P36009, P42789, P48053, P56523, P93834, Q06010, Q10040, Q10068, Q12496, Q16P87, Q24K02, Q26609, Q28BR5, Q2UGN1, Q42525, Q4WP38, Q54JQ2, Q5JRX3, Q5RDG3, Q61E36, Q655R6, Q6CWW6, Q6FUI7, Q6PF24, Q759T9

Diamond homologs: O42908, P32898, Q28BR5, Q2UGN1, Q4IA56, Q4WP38, Q5A301, Q5B6H7, Q5JRX3, Q5RDG3, Q6BTC0, Q6C0U8, Q6CWW6, Q6FUI7, Q6PF24, Q759T9, Q7S7C0, Q7ZVZ6, Q8K411, Q8VY06, Q9LJL3, Q9V9E3, F4HNU6, P48053, Q12496, Q10068, Q46205, Q9FX93

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PITRM1	“down-regulates activity”	APP	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 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 protein import	6	12.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	305
Likely benign	127
Benign	53

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1120050	NM_014889.4(PITRM1):c.2236-1dup	Pathogenic
1175723	NM_014889.4(PITRM1):c.548G>A (p.Arg183Gln)	Pathogenic
202235	GRCh37/hg19 10p15.3-15.1(chr10:138878-5160945)x3	Pathogenic
4537358	NM_002726.5(PREP):c.1570_1573dup (p.Asn525fs)	Pathogenic
4537359	NM_002726.5(PREP):c.1839-2A>G	Pathogenic
3337460	NM_014889.4(PITRM1):c.2423del (p.Lys808fs)	Likely pathogenic

SpliceAI

8795 predictions. Top by Δscore:

Variant	Effect	Δscore
10:3138231:TCACC:T	donor_loss	1.0000
10:3138233:ACCT:A	donor_loss	1.0000
10:3139048:CC:C	acceptor_gain	1.0000
10:3139049:CC:C	acceptor_gain	1.0000
10:3139060:C:CT	acceptor_gain	1.0000
10:3139060:C:T	acceptor_gain	1.0000
10:3139061:A:T	acceptor_gain	1.0000
10:3140682:CTCA:C	donor_loss	1.0000
10:3140683:TCAC:T	donor_loss	1.0000
10:3140684:CACC:C	donor_loss	1.0000
10:3140808:TAAGA:T	acceptor_gain	1.0000
10:3140810:AGA:A	acceptor_gain	1.0000
10:3140811:GA:G	acceptor_gain	1.0000
10:3140813:C:CC	acceptor_gain	1.0000
10:3144383:C:CT	acceptor_gain	1.0000
10:3145591:CATA:C	donor_loss	1.0000
10:3145592:ATAC:A	donor_loss	1.0000
10:3145593:TACC:T	donor_loss	1.0000
10:3145594:A:AG	donor_loss	1.0000
10:3145597:TCG:T	donor_gain	1.0000
10:3145627:T:A	donor_gain	1.0000
10:3145714:CAC:C	acceptor_gain	1.0000
10:3145715:AC:A	acceptor_gain	1.0000
10:3145716:CC:C	acceptor_gain	1.0000
10:3145717:C:CC	acceptor_gain	1.0000
10:3145718:T:G	acceptor_loss	1.0000
10:3145721:T:C	acceptor_gain	1.0000
10:3145870:C:CA	donor_gain	1.0000
10:3147558:T:TA	donor_gain	1.0000
10:3147567:C:A	donor_gain	1.0000

AlphaMissense

6888 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:3138958:C:G	A955P	0.998
10:3140759:C:G	R900P	0.997
10:3165320:C:G	R183P	0.997
10:3166324:T:G	H108P	0.996
10:3138285:T:A	R990S	0.995
10:3138285:T:G	R990S	0.995
10:3165470:A:G	L159P	0.995
10:3165254:T:A	E205V	0.994
10:3165270:C:G	G200R	0.994
10:3165270:C:T	G200R	0.994
10:3166326:C:A	E107D	0.994
10:3166326:C:G	E107D	0.994
10:3165253:C:A	E205D	0.993
10:3165253:C:G	E205D	0.993
10:3165263:A:T	V202D	0.993
10:3165326:C:T	G181E	0.993
10:3165483:C:G	D155H	0.993
10:3166261:C:G	R129P	0.993
10:3166323:A:C	H108Q	0.993
10:3166323:A:T	H108Q	0.993
10:3166325:G:C	H108D	0.993
10:3166380:G:C	S89R	0.993
10:3166380:G:T	S89R	0.993
10:3166937:T:G	S89R	0.993
10:3163767:A:G	L250P	0.992
10:3165269:C:T	G200E	0.992
10:3167002:A:G	L67P	0.992
10:3140693:G:A	S922F	0.991
10:3140744:G:T	A905D	0.991
10:3148006:A:G	W684R	0.991

dbSNP variants (sampled 300 via entrez): RS1000057675 (10:3166486 C>A,G,T), RS1000353912 (10:3155053 C>T), RS1000485017 (10:3143100 G>C), RS1000547062 (10:3157293 T>C), RS1000594438 (10:3154014 C>T), RS1000626140 (10:3142883 G>A), RS1000682620 (10:3153755 A>G), RS1000685795 (10:3152301 G>A), RS1000802140 (10:3170898 G>A), RS1000899124 (10:3164210 G>A), RS1000908947 (10:3164046 C>A,T), RS1001056843 (10:3138198 C>A,T), RS1001059129 (10:3167443 C>T), RS1001118609 (10:3137987 G>A), RS1001221964 (10:3145209 G>C)

Disease associations

OMIM: gene MIM:618211 | disease phenotypes: MIM:271245, MIM:619405, MIM:604229

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 30	Strong	Autosomal recessive

Mondo (4): mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (MONDO:0010060), spinocerebellar ataxia, autosomal recessive 30 (MONDO:0030318), cerebellar ataxia (MONDO:0000437), Peters anomaly (MONDO:0011414)

Orphanet (3): Infantile-onset spinocerebellar ataxia (Orphanet:1186), Rare ataxia (Orphanet:102002), Peters anomaly (Orphanet:708)

HPO phenotypes

20 total (21 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000722	Compulsive behaviors
HP:0000725	Psychotic episodes
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001348	Brisk reflexes
HP:0002059	Cerebral atrophy
HP:0002151	Increased circulating lactate concentration
HP:0002317	Unsteady gait
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003542	Increased circulating pyruvate concentration
HP:0003593	Infantile onset
HP:0011463	Childhood onset
HP:0025435	Increased circulating lactate dehydrogenase concentration
HP:0030187	Titubation
HP:0000659	Peters anomaly

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST000253_14	Attention deficit hyperactivity disorder and conduct disorder	9.000000e-06
GCST003474_6	Scalp hair shape	3.000000e-06
GCST003475_6	Beard thickness	4.000000e-08
GCST003831_36	Asthma	7.000000e-06
GCST005351_6	Carboplatin disposition in epthelial ovarian cancer	7.000000e-06
GCST006585_2262	Blood protein levels	7.000000e-44
GCST009016_4	T wave morphology restitution during exercise	8.000000e-07
GCST009068_4	T wave morphology restitution during exercise (MTAG)	4.000000e-08
GCST009173_2	Response to (pegylated) interferon in HBeAG-positive hepatitis B	4.000000e-06
GCST009391_157	Metabolite levels	7.000000e-06
GCST009391_1591	Metabolite levels	5.000000e-06
GCST009391_1607	Metabolite levels	5.000000e-06
GCST009391_1727	Metabolite levels	8.000000e-06
GCST009391_1791	Metabolite levels	9.000000e-07
GCST009391_2106	Metabolite levels	8.000000e-06
GCST009597_13	Multiple sclerosis	1.000000e-06
GCST010796_3835	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3836	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_3837	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3838	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_3839	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_3840	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_3841	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_3842	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_3843	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_3844	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3845	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-09
GCST010796_3846	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3847	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3848	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0008398	T wave morphology measurement
EFO:0007859	response to interferon
EFO:0010486	glucuronate measurement
EFO:0010376	phosphatidylcholine 34:2 measurement
EFO:0010377	phosphatidylcholine 34:3 measurement
EFO:0010374	phosphatidylcholine 32:2 measurement
EFO:0010449	3-methyladipic acid measurement
EFO:0010524	pimelic acid measurement
EFO:0010373	phosphatidylcholine 32:1 measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
C535523	Infantile onset spinocerebellar ataxia (supp.)
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3124731 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 10,259 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL67279	TALABOSTAT	3	10,259

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

Binding affinities (BindingDB)

2 measured of 2 human assays (3 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-7-methylquinoline-4-carboxamide	IC50	5.2 nM	US-20250368637: SOLID-STATE FORMS OF N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-6-MORPHOLINOQUINOLINE-4-CARBOXAMIDE
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]quinoline-4-carboxamide	IC50	7.1 nM	US-20250368637: SOLID-STATE FORMS OF N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-6-MORPHOLINOQUINOLINE-4-CARBOXAMIDE

ChEMBL bioactivities

21 potent at pChembl≥5 of 22 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	EC50	12	nM	CHEMBL3127264
7.82	IC50	15	nM	CHEMBL6020304
7.64	IC50	23	nM	CHEMBL6004569
7.47	IC50	34	nM	CHEMBL5981431
7.38	IC50	42	nM	CHEMBL6059875
7.31	IC50	49	nM	CHEMBL5957037
7.24	EC50	57	nM	CHEMBL3127263
7.24	IC50	58	nM	CHEMBL5925037
7.17	IC50	68	nM	CHEMBL5968328
6.82	EC50	152	nM	CHEMBL3127264
6.70	IC50	200	nM	CHEMBL5809136
6.40	EC50	402	nM	CHEMBL3127263
6.22	EC50	601	nM	CHEMBL3127263
6.15	EC50	713	nM	CHEMBL3127264
6.14	IC50	730	nM	CHEMBL5817549
5.92	IC50	1200	nM	CHEMBL5848496
5.85	IC50	1400	nM	CHEMBL5778991
5.26	IC50	5500	nM	TALABOSTAT
5.26	IC50	5500	nM	CHEMBL3233842

PubChem BioAssay actives

6 with measured affinity, of 31 total; 2 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-bromo-2-[[2-(5-bromo-2-hydroxyphenyl)-6-nitrobenzimidazol-1-yl]methyl]phenol	1077210: Agonist activity at human PreP assessed as degradation of ATP synthase pF1beta subunit (2 to 56) after 2.5 hrs by Immunoblotting assay	ec50	0.0120	uM
4-bromo-2-[[2-(5-bromo-2-hydroxyphenyl)-3-[(5-bromo-2-hydroxyphenyl)methyl]-5-nitro-2H-benzimidazol-1-yl]methyl]phenol	1077209: Agonist activity at human PreP assessed as degradation of fluorogenic substrate V measured for 10 mins by fluorometric analysis	ec50	0.0570	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	affects cotreatment, decreases expression, increases expression	2
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
Acetaminophen	increases expression	2
Valproic Acid	affects expression, increases methylation	2
Cyclosporine	increases expression, increases methylation	2
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	increases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
bazedoxifene	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	increases abundance, increases expression	1
Vehicle Emissions	affects expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Furaldehyde	decreases expression, affects cotreatment, affects localization, increases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Sodium Chloride	affects cotreatment, decreases expression, affects localization, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3128913	Binding	Agonist activity at human PreP assessed as degradation of fluorogenic substrate V at 1 uM measured for 10 mins by fluorometric analysis	Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer’s disease. — Eur J Med Chem

Clinical trials (associated diseases)

146 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
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
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
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT01104649	PHASE2/PHASE3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT00244361	PHASE1/PHASE2	COMPLETED	Effectiveness of Rituximab in Pediatric OMS Patients.
NCT01649687	PHASE1/PHASE2	COMPLETED	Treatment of Cerebellar Ataxia With Mesenchymal Stem Cells
NCT01958177	PHASE1/PHASE2	UNKNOWN	Clinical Study to Evaluate the Safety and Efficacy BMMNC in Cerebellar Ataxia
NCT02829268	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00006492	Not specified	COMPLETED	Gluten-Free Diet in Patients With Gluten Sensitivity and Cerebellar Ataxia
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00272272	Not specified	COMPLETED	Fall Prevention in a Geriatric Nursing Home Setting Using the Music of Nolwenn Leroy
NCT00654251	Not specified	COMPLETED	Measuring Neurological Impairment and Functional Visual Assessment In Spinocerebellar Ataxias
NCT00692861	Not specified	COMPLETED	Autoimmunity in Neurologic Complications of Celiac Disease
NCT01037777	Not specified	COMPLETED	RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7
NCT01307176	Not specified	COMPLETED	Exercise Training Program for Cerebellar Ataxia
NCT01428531	Not specified	COMPLETED	Special Drug Use Investigation for Arixtra® (Fondaparinux) Venous Thromboembolism Treatment