HTRA2

Summary

HTRA2 (HtrA serine peptidase 2, HGNC:14348) is a protein-coding gene on chromosome 2p13.1, encoding Serine protease HTRA2, mitochondrial (O43464). Serine protease that shows proteolytic activity against a non-specific substrate beta-casein.

This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 27429 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylglutaconic aciduria type 8 (Definitive, ClinGen)
• Clinical variants (ClinVar): 345 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 70
• Druggable target: yes
• MANE Select transcript: NM_013247

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14348
Approved symbol	HTRA2
Name	HtrA serine peptidase 2
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	OMI, PARK13
Ensembl gene	ENSG00000115317
Ensembl biotype	protein_coding
OMIM	606441
Entrez	27429

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 7 retained_intron, 6 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000258080, ENST00000352222, ENST00000437202, ENST00000462909, ENST00000465521, ENST00000467961, ENST00000482205, ENST00000482331, ENST00000484352, ENST00000484881, ENST00000696725, ENST00000696726, ENST00000696727, ENST00000696728, ENST00000696729, ENST00000696730, ENST00000696731, ENST00000854416, ENST00000854417

RefSeq mRNA: 4 — MANE Select: NM_013247 NM_001321727, NM_001321728, NM_013247, NM_145074

CCDS: CCDS1951, CCDS1952, CCDS92785, CCDS92786

Canonical transcript exons

ENST00000258080 — 8 exons

Exon	Start	End
ENSE00000920849	74532820	74533319
ENSE00001276828	74529933	74530512
ENSE00003557589	74531597	74531702
ENSE00003573102	74531856	74531925
ENSE00003578709	74530911	74531105
ENSE00003599050	74532619	74532714
ENSE00003637787	74531339	74531371
ENSE00003670137	74530617	74530821

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 92.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1520 / max 325.9846, expressed in 1798 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21053	10.3116	1758
21057	3.2809	1326
21054	1.3395	937
21055	0.7641	409
21056	0.4589	259
21060	0.3344	54
21052	0.1311	44
21049	0.1223	67
21059	0.1131	35
21051	0.1113	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.01	gold quality
right coronary artery	UBERON:0001625	91.90	gold quality
trabecular bone tissue	UBERON:0002483	91.79	gold quality
ganglionic eminence	UBERON:0004023	91.38	gold quality
apex of heart	UBERON:0002098	91.37	gold quality
mucosa of transverse colon	UBERON:0004991	91.35	gold quality
granulocyte	CL:0000094	91.16	gold quality
spleen	UBERON:0002106	90.99	gold quality
right ovary	UBERON:0002118	90.81	gold quality
ascending aorta	UBERON:0001496	90.77	gold quality
thoracic aorta	UBERON:0001515	90.75	gold quality
omental fat pad	UBERON:0010414	90.73	gold quality
left coronary artery	UBERON:0001626	90.72	gold quality
peritoneum	UBERON:0002358	90.71	gold quality
coronary artery	UBERON:0001621	90.70	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.68	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.66	gold quality
prefrontal cortex	UBERON:0000451	90.55	gold quality
right frontal lobe	UBERON:0002810	90.53	gold quality
mucosa of stomach	UBERON:0001199	90.49	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.46	gold quality
lower esophagus	UBERON:0013473	90.44	gold quality
left ovary	UBERON:0002119	90.42	gold quality
right adrenal gland	UBERON:0001233	90.25	gold quality
aorta	UBERON:0000947	90.22	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.18	gold quality
left adrenal gland	UBERON:0001234	90.13	gold quality
left adrenal gland cortex	UBERON:0035825	90.13	gold quality
body of uterus	UBERON:0009853	90.03	gold quality
descending thoracic aorta	UBERON:0002345	90.02	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	45.19
E-ANND-3	yes	6.15
E-CURD-11	no	59.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, WT1

miRNA regulators (miRDB)

20 targeting HTRA2, 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-12118	100.00	65.88	1270
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-4278	95.28	65.49	351

Literature-anchored findings (GeneRIF, showing 40)

• 2.0 A crystal structure; structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi (PMID:11967569)
• these results indicate that unlike Smac/DIABLO, Omi/HtrA2’s catalytic cleavage of IAPs is a key mechanism for it to irreversibly inactivate IAPs and promote apoptosis. (PMID:12815069)
• identification of inhibitor of apoptosis proteins as substrate (PMID:12835328)
• protease activity of Omi/HtrA2 promotes caspase activation through multiple pathways (PMID:14605674)
• mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate (PMID:14645012)
• Amyloid-beta interacts with HtrA2/Omi, an essential human serine protease with proapoptotic activity. Additionally, we mapped the C-terminal region containing the PDZ domain of HtrA2/Omi as the binding determinant for Abeta. (PMID:15036614)
• autocatalytic processing of HtrA2/Omi is crucial for regulating HtrA2/Omi-mediated apoptotic cell death (PMID:15201285)
• effect of temperature on proteolytic activity of HtrA2 and related structural properties were investigated (PMID:15236609)
• C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. (PMID:15294909)
• apoptosis following Omi/HtrA2 mitochondrial release is mediated by reduction in ped/pea-15 cellular levels (PMID:15328349)
• On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD. (PMID:15961413)
• Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. (PMID:16968707)
• Mediates processing of WARTS mitotic kinase in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis. (PMID:17130845)
• HtrA2/Omi has a rather narrow cleavage site preference and cytoskeletal proteins are prime targets of this protease. (PMID:17266347)
• HtrA2 has a role as a regulator of APP metabolism through endoplasmic reticulum-associated degradation (PMID:17684015)
• This article summarizes recent studies regarding the HtrA family of proteins, their structure, regulation and function. It also presents practical applications of this knowledge and perspective of its use in the future. (PMID:17718385)
• expression of Smac/DIABLO, but not Omi/HtrA2, is inversely associated with outcome of renal cell carcinoma patients. (PMID:17922292)
• These data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins. (PMID:18060880)
• A significant downregulation of HtrA2 transcription is found in the group of borderline tumors of the ovary; HtrA2 may function as a tumor suppressor. (PMID:18241672)
• Data show that following apoptotic stimuli, HtrA2 accumulates in the nucleus and cleaves p73alpha in the C-terminal portion, enabling the protein to increase its transactivation activity on Bax but not on the cell-cycle regulator gene p21. (PMID:18259191)
• elimination of excess or spontaneously misfolded wild-type intermembrane space proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient (PMID:18362145)
• Polymorphism of OMI/HTRA2 previously shown to be associated with Parkinson’s disease was present in the neurologically normal controls. (PMID:18364387)
• The study of HTRA2 to Parkinson disease risk in an extended series of 266 Belgian PD patients and 273 control individuals identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. (PMID:18401856)
• Omi/Htra2 serine protease activity participates in the cell death induced by CDDP but not of 5-FU in colon cancer cells. (PMID:18606591)
• These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology. (PMID:18662332)
• HtrA2/Omi sensitizes cytomegalovirus infected cells to death that can be blocked by vMIA or protease inhibitors (PMID:18769594)
• the results of this study do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinson’s disease. (PMID:18790661)
• HtrA2/Omi may be associated with the pathogenesis of alpha-synucleinopathies (PMID:18800009)
• These data suggest that a down-regulation of Smac/DIABLO and HtrA2 is implicated in the development and progression of TGCT, whereas overexpression of XAF1 in TGCT might contribute to their extraordinary sensitivity to chemotherapy. (PMID:18979398)
• Point mutations in another mitochondrial protein, HtrA2, are a susceptibility factor for Parkinson disease (PARK13 locus) (PMID:19076428)
• This study found that no associations were seen for HTRA2 in Australia patient with Parkinson’s disease (PMID:19224617)
• This review introduces HtrA2 from its molecular origins and discusses its modulation and potential as a novel drug target. (PMID:19355862)
• HtrA2 was down-regulated in endometrial cancers. (PMID:19424634)
• THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes (PMID:19502560)
• Translocation of Omi/HtrA2 from mitochondria into cytoplasm may play an important role in its intracellular signal transduction mechanism in induction of apoptosis. (PMID:19570340)
• Studies show that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis. (PMID:19656851)
• results indicate a different function and mechanism of Hax1 in apoptosis and re-opens the question of whether mammalian PARL, in addition to apoptosis, regulates mitochondrial stress response through Omi/HtrA2 processing. (PMID:19680265)
• omi has a regulatory role in neurodegenerative disorders (PMID:19763263)
• PINK1, Omi/HtrA2 and parkin participate at different levels in mitochondrial quality control, converging through some overlapping and some distinct steps to maintain a common phenotype of healthy mitochondrial networks [REVIEW] (PMID:20012177)
• This largest association study performed revealed no overall strong association of Omi/HtrA2 variants with Parkinson dusease in populations worldwide. (PMID:20036034)

Cross-species orthologs

28 orthologs

Organism	Symbol	Gene ID
danio_rerio	htra2-9	ENSDARG00000069909
danio_rerio		ENSDARG00000070138
danio_rerio	htra2-12	ENSDARG00000076713
danio_rerio	si:dkey-271n12.1	ENSDARG00000088743
danio_rerio	htra2-3	ENSDARG00000092061
danio_rerio	htra2-2	ENSDARG00000092094
danio_rerio	HTRA2	ENSDARG00000092133
danio_rerio	htra2-6	ENSDARG00000092202
danio_rerio	htra2-11	ENSDARG00000092380
danio_rerio	si:dkey-10b15.8	ENSDARG00000092625
danio_rerio	htra2-8	ENSDARG00000093005
danio_rerio	htra2-5	ENSDARG00000094236
danio_rerio	htra2-7	ENSDARG00000094403
danio_rerio	htra2-10	ENSDARG00000094741
danio_rerio	HTRA2	ENSDARG00000094749
danio_rerio	si:dkey-84o3.8	ENSDARG00000094878
danio_rerio	HTRA2	ENSDARG00000094995
danio_rerio	si:dkey-112g5.14	ENSDARG00000095314
danio_rerio	HTRA2	ENSDARG00000095545
danio_rerio	si:dkey-84o3.7	ENSDARG00000095687
danio_rerio	htra2-4	ENSDARG00000111633
danio_rerio		ENSDARG00000114913
danio_rerio	HTRA2	ENSDARG00000115106
danio_rerio	htra2-1	ENSDARG00000115120
danio_rerio		ENSDARG00000116494
mus_musculus	Htra2	ENSMUSG00000068329
rattus_norvegicus	Htra2	ENSRNOG00000022448
drosophila_melanogaster	HtrA2	FBGN0038233

Paralogs (3): HTRA1 (ENSG00000166033), HTRA4 (ENSG00000169495), HTRA3 (ENSG00000170801)

Protein

Protein identifiers

Serine protease HTRA2, mitochondrial — O43464 (reviewed: O43464)

Alternative names: High temperature requirement protein A2, Omi stress-regulated endoprotease, Serine protease 25, Serine proteinase OMI

All UniProt accessions (5): O43464, A0A0C4DG44, A0A384MDW9, A0A8Q3SIX7, A0A8Q3SJ36

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes apoptosis by either relieving the inhibition of BIRC proteins on caspases, leading to an increase in caspase activity; or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves BIRC6 and relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone to inhibition by BIRC6. Cleaves THAP5 and promotes its degradation during apoptosis. Seems to be proteolytically inactive.

Subunit / interactions. Homotrimer. Interacts with MXI2. Interacts with THAP5 under apoptotic conditions. The mature protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis.

Subcellular location. Mitochondrion intermembrane space. Mitochondrion membrane Endoplasmic reticulum.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC. Autoproteolytically activated.

Disease relevance. 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248] An autosomal recessive inborn error of metabolism resulting in early death. Clinical features include extreme hypertonia observed at birth, alternating with hypotonia, subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, and intractable seizures. Patients show lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, and progressive brain atrophy. The disease is caused by variants affecting the gene represented in this entry. Parkinson disease 13 (PARK13) [MIM:610297] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Inhibited by BIRC6.

Domain organisation. The mature N-terminus is involved in the interaction with XIAP. The PDZ domain mediates interaction with MXI2.

Similarity. Belongs to the peptidase S1C family.

Isoforms (4)

UniProt ID	Names	Canonical?
O43464-1	1, 13B	yes
O43464-2	2, D-Omi
O43464-3	3, p7
O43464-4	4, p4

RefSeq proteins (4): NP_001308656, NP_001308657, NP_037379, NP_659540 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001940	Peptidase_S1C	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain

Pfam: PF13365, PF17820

Enzyme classification (BRENDA):

• EC 3.4.21.108 — HtrA2 peptidase (BRENDA: 23 organisms, 127 substrates, 42 inhibitors, 35 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BETA-CASEIN	0.001–0.0093	24
ALA(7-METHOXYCOUMARIN-4-ACETIC ACID)-IRRVSYSF-(5	0.0007–0.001	3
(7-METHOXYCOUMARIN-4-YL)AIRRVSYSF-(5-AMINO-2-NIT	0.0016	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-HIS-	0.0391	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-PHE-	0.0227	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-TRP-	0.107	1
2-AMINOBENZOIC ACID-ILE-MET-THR-SER-TYR-MET-PHE-	0.354	1
2-AMINOBENZOIC ACID-ILE-MET-VAL-ABU-TYR-MET-PHE-	0.0315	1
2-AMINOBENZOIC ACID-ILE-MET-VAL-SER-TYR-MET-PHE-	0.177	1
OLIGOMERIC ALPHA-SYNUCLEIN	0.0026	1
SPMFKGV-PARA-NITROANILINE	—	0

UniProt features (60 total): strand 22, sequence variant 9, helix 9, splice variant 4, turn 4, active site 3, mutagenesis site 2, transit peptide 1, propeptide 1, chain 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
5M3N	X-RAY DIFFRACTION	1.65
5TO1	X-RAY DIFFRACTION	1.69
5M3O	X-RAY DIFFRACTION	1.7
5TNY	X-RAY DIFFRACTION	1.7
5TNZ	X-RAY DIFFRACTION	1.75
5TO0	X-RAY DIFFRACTION	1.9
5FHT	X-RAY DIFFRACTION	1.95
1LCY	X-RAY DIFFRACTION	2
5WYN	X-RAY DIFFRACTION	2.05
2PZD	X-RAY DIFFRACTION	2.75
8E2K	ELECTRON MICROSCOPY	3.21
7VGE	X-RAY DIFFRACTION	4
8AUK	ELECTRON MICROSCOPY	6.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43464-F1	74.83	0.51

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 (3): 198 (charge relay system); 228 (charge relay system); 306 (charge relay system)

Mutagenesis-validated functional residues (2):

Position	Phenotype
134	loss of interaction with xiap. loss of inhibition of xiap activity.
306	loss of protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)

MSigDB gene sets: 447 (showing top): MODULE_52, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_ADULT_BEHAVIOR, MODULE_45, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (34): proteolysis (GO:0006508), ceramide metabolic process (GO:0006672), mitochondrion organization (GO:0007005), adult walking behavior (GO:0007628), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), response to herbicide (GO:0009635), programmed cell death (GO:0012501), protein autoprocessing (GO:0016540), pentacyclic triterpenoid metabolic process (GO:0019742), protein catabolic process (GO:0030163), forebrain development (GO:0030900), cellular response to oxidative stress (GO:0034599), cellular response to heat (GO:0034605), cellular response to interferon-beta (GO:0035458), intracellular signal transduction (GO:0035556), mitochondrial protein catabolic process (GO:0035694), regulation of multicellular organism growth (GO:0040014), positive regulation of apoptotic process (GO:0043065), negative regulation of neuron apoptotic process (GO:0043524), negative regulation of cell cycle (GO:0045786), neuron development (GO:0048666), neuron apoptotic process (GO:0051402), cellular response to retinoic acid (GO:0071300), cellular response to growth factor stimulus (GO:0071363), execution phase of apoptosis (GO:0097194), positive regulation of execution phase of apoptosis (GO:1900119), negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902176), regulation of autophagy of mitochondrion (GO:1903146), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), negative regulation of type 2 mitophagy (GO:1905090), positive regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001241), apoptotic process (GO:0006915), adult locomotory behavior (GO:0008344), intrinsic apoptotic signaling pathway (GO:0097193)

GO Molecular Function (9): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), protein serine/threonine kinase inhibitor activity (GO:0030291), identical protein binding (GO:0042802), obsolete unfolded protein binding (GO:0051082), ubiquitin ligase inhibitor activity (GO:1990948), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (14): chromatin (GO:0000785), nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoskeleton (GO:0005856), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), mitochondrial membrane (GO:0031966), CD40 receptor complex (GO:0035631), serine-type endopeptidase complex (GO:1905370), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membrane-bounded organelle	3
cytoplasm	3
protein metabolic process	2
signal transduction	2
mitochondrion	2
mitochondrial envelope	2
organelle membrane	2
sphingolipid metabolic process	1
organelle organization	1
adult locomotory behavior	1
walking behavior	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
response to stress	1
response to toxic substance	1
cell death	1
protein processing	1
triterpenoid metabolic process	1
macromolecule catabolic process	1
brain development	1
anatomical structure development	1
response to oxidative stress	1
cellular response to chemical stress	1
response to heat	1
cellular response to stress	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
intracellular anatomical structure	1
mitochondrion organization	1
protein catabolic process	1
multicellular organism growth	1
regulation of developmental growth	1
regulation of multicellular organismal process	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1

Protein interactions and networks

STRING

2916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTRA2	DIABLO	Q9NR28	934
HTRA2	XIAP	P98170	923
HTRA2	PINK1	Q9BXM7	915
HTRA2	PARL	Q9H300	910
HTRA2	A0A1W2PP11	A0A1W2PP11	907
HTRA2	HAX1	O00165	864
HTRA2	RBMX	P38159	840
HTRA2	PRKN	O60260	820
HTRA2	APAF1	O14727	814
HTRA2	PSEN1	P49768	813
HTRA2	ENDOG	Q14249	807
HTRA2	GIGYF2	Q6Y7W6	794
HTRA2	FBXO7	Q9Y3I1	773
HTRA2	CYCS	P00001	768
HTRA2	BIRC2	Q13490	767

IntAct

728 interactions, top by confidence:

A	B	Type	Score
HTRA2	XIAP	psi-mi:“MI:0570”(protein cleavage)	0.960
XIAP	HTRA2	psi-mi:“MI:0194”(cleavage reaction)	0.960
HTRA2	CSN2	psi-mi:“MI:0570”(protein cleavage)	0.800
CSN2	HTRA2	psi-mi:“MI:0194”(cleavage reaction)	0.800
HTRA2	NDUFA13	psi-mi:“MI:0915”(physical association)	0.750
NDUFA13	HTRA2	psi-mi:“MI:0915”(physical association)	0.750
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
TTC19	HTRA2	psi-mi:“MI:0915”(physical association)	0.660
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
PHOX2A	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
TEN1	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
ERCC8	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
CRYAA	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
ID2	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
KRT19	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
KRT33B	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
MAP3K5	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
NEUROD1	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
NVL	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
HTRA2	PSMC3	psi-mi:“MI:0915”(physical association)	0.560
SMARCD1	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
HTRA2	SMN1	psi-mi:“MI:0915”(physical association)	0.560
ZBTB25	HTRA2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (379): HTRA2 (Affinity Capture-Western), HTRA2 (Affinity Capture-MS), HTRA2 (Affinity Capture-MS), HTRA2 (Affinity Capture-MS), HTRA2 (Affinity Capture-MS), HTRA2 (Affinity Capture-MS), CSN2 (Biochemical Activity), XIAP (Reconstituted Complex), XIAP (Protein-peptide), HTRA2 (Reconstituted Complex), ASS1 (Co-fractionation), DSTN (Co-fractionation), GOT1 (Co-fractionation), HTRA2 (Co-fractionation), HTRA2 (Co-fractionation)

ESM2 similar proteins: A0JNK3, A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D3ZA76, D3ZKF5, E1BJW1, F1N152, F4J3G5, O22609, O23614, O43464, P14543, P38935, P73940, P83105, P83110, Q14689, Q14703, Q297U2, Q3U213, Q5SNQ7, Q5XIL0, Q6GMI0, Q852K0, Q8BMS2, Q8IUL8, Q8IZJ1, Q91XF4

Diamond homologs: A0JNK3, A2RNT9, A2RT60, A4IHA1, A4XSC0, A5W8F5, A6VUA4, A6YFB5, A9JRB3, B0KV30, B1J4D7, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D0ZY51, D3ZA76, D3ZKF5, E1BJW1, E1V4H2, F1N152, F6AA62, O05942, O06291, O22609, O34358, O43464, O53896, O85291, P05676, P0A3Z5, P0AEE3, P0AEE4, P0C0V0

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
HTRA2	down-regulates	XIAP	binding
BAK1	up-regulates	HTRA2	relocalization
HTRA2	down-regulates	PEA15	binding
AKT	down-regulates	HTRA2	phosphorylation
AKT2	down-regulates	HTRA2	phosphorylation
PINK1	up-regulates	HTRA2	phosphorylation
BAK1	up-regulates	HTRA2
CDK5	up-regulates	HTRA2	phosphorylation
AKT1	down-regulates	HTRA2	phosphorylation
AREL1	“down-regulates quantity by destabilization”	HTRA2	ubiquitination
BAX	up-regulates	HTRA2	relocalization
BCL2	down-regulates	HTRA2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Aerobic respiration and respiratory electron transport	7	11.9×	2e-04
Neddylation	8	7.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	9	6.0×	4e-03
protein ubiquitination	11	5.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	142
Likely benign	147
Benign	10

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1424738	NM_013247.5(HTRA2):c.244C>T (p.Gln82Ter)	Pathogenic
1452577	NM_013247.5(HTRA2):c.949del (p.Glu316_Val317insTer)	Pathogenic
1455851	NM_013247.5(HTRA2):c.1138C>T (p.Arg380Ter)	Pathogenic
2799046	NM_013247.5(HTRA2):c.403_419dup (p.Ala141fs)	Pathogenic
2875923	NM_013247.5(HTRA2):c.139dup (p.Arg47fs)	Pathogenic
372210	NM_013247.5(HTRA2):c.1316_1320del (p.Val439fs)	Pathogenic
372211	NM_013247.5(HTRA2):c.906+1G>C	Pathogenic
372212	NM_013247.5(HTRA2):c.728_730delinsCAT (p.Leu243_Pro244delinsProSer)	Pathogenic
4697380	NM_013247.5(HTRA2):c.336_342dup (p.Gly115fs)	Pathogenic
4772221	NM_013247.5(HTRA2):c.587dup (p.Asn196fs)	Pathogenic
1252041	NM_013247.5(HTRA2):c.1013_1015del (p.Leu338del)	Likely pathogenic
3384181	NM_013247.5(HTRA2):c.1216G>T (p.Gly406Cys)	Likely pathogenic
3586941	NM_013247.5(HTRA2):c.420del (p.Ala141fs)	Likely pathogenic
4715258	NM_013247.5(HTRA2):c.506+1G>C	Likely pathogenic

SpliceAI

977 predictions. Top by Δscore:

Variant	Effect	Δscore
2:74530610:A:AG	acceptor_gain	1.0000
2:74530611:T:G	acceptor_gain	1.0000
2:74530613:TCAG:T	acceptor_loss	1.0000
2:74530615:A:AG	acceptor_gain	1.0000
2:74530615:A:C	acceptor_loss	1.0000
2:74530615:AG:A	acceptor_gain	1.0000
2:74530616:G:A	acceptor_gain	1.0000
2:74530616:G:GA	acceptor_gain	1.0000
2:74530616:GGC:G	acceptor_gain	1.0000
2:74530616:GGCA:G	acceptor_gain	1.0000
2:74530616:GGCAC:G	acceptor_gain	1.0000
2:74530803:GC:G	donor_gain	1.0000
2:74530804:C:G	donor_gain	1.0000
2:74530809:GAT:G	donor_gain	1.0000
2:74530817:C:CG	donor_gain	1.0000
2:74530817:C:G	donor_gain	1.0000
2:74530819:AAGGT:A	donor_loss	1.0000
2:74530820:AGG:A	donor_loss	1.0000
2:74530821:GG:G	donor_loss	1.0000
2:74530823:T:G	donor_loss	1.0000
2:74531098:C:G	donor_gain	1.0000
2:74531106:G:GG	donor_gain	1.0000
2:74531121:A:T	donor_gain	1.0000
2:74531698:GAAGA:G	donor_gain	1.0000
2:74531701:GA:G	donor_gain	1.0000
2:74531703:G:GG	donor_gain	1.0000
2:74531853:CA:C	acceptor_loss	1.0000
2:74531854:AG:A	acceptor_loss	1.0000
2:74532614:TTCA:T	acceptor_loss	1.0000
2:74532615:TCAG:T	acceptor_loss	1.0000

AlphaMissense

2869 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:74530793:A:T	D228V	1.000
2:74530959:G:A	G254R	1.000
2:74530959:G:C	G254R	1.000
2:74530960:G:A	G254E	1.000
2:74530969:T:A	V257D	1.000
2:74531017:G:A	G273D	1.000
2:74531017:G:T	G273V	1.000
2:74531023:T:A	V275D	1.000
2:74531025:A:C	S276R	1.000
2:74531027:C:A	S276R	1.000
2:74531027:C:G	S276R	1.000
2:74531083:T:A	I295N	1.000
2:74531087:A:C	Q296H	1.000
2:74531087:A:T	Q296H	1.000
2:74531347:C:A	N305K	1.000
2:74531347:C:G	N305K	1.000
2:74531352:G:A	G307E	1.000
2:74531352:G:T	G307V	1.000
2:74531361:T:C	L310P	1.000
2:74531364:T:A	V311D	1.000
2:74531368:C:A	N312K	1.000
2:74531368:C:G	N312K	1.000
2:74531612:G:A	G319R	1.000
2:74531612:G:C	G319R	1.000
2:74531613:G:A	G319E	1.000
2:74531648:T:C	F331L	1.000
2:74531650:T:A	F331L	1.000
2:74531650:T:G	F331L	1.000
2:74531652:C:A	A332D	1.000
2:74530455:T:A	I150N	0.999

dbSNP variants (sampled 300 via entrez): RS1003110928 (2:74533064 A>G), RS1005091109 (2:74533000 G>C), RS1005850181 (2:74527933 C>T), RS1007566292 (2:74533728 A>G), RS1007639725 (2:74533493 T>C), RS1007852428 (2:74530519 G>A), RS1008997759 (2:74532112 C>G,T), RS1009274930 (2:74532478 G>A), RS1010767431 (2:74532049 A>G), RS1010979891 (2:74530448 A>C,G), RS1011907378 (2:74533410 C>A,T), RS1012007138 (2:74531541 GC>G), RS1012038303 (2:74531186 G>A), RS1012713980 (2:74528242 T>A), RS1013074327 (2:74528596 G>A)

Disease associations

OMIM: gene MIM:606441 | disease phenotypes: MIM:617248, MIM:610297, MIM:256000, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 8	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 8	Definitive	AR

Mondo (5): 3-methylglutaconic aciduria type 8 (MONDO:0044723), Parkinson disease 13, autosomal dominant, susceptibility to (MONDO:0012466), breast ductal adenocarcinoma (MONDO:0005590), Leigh syndrome (MONDO:0009723), autism (MONDO:0005260)

Orphanet (3): 3-methylglutaconic aciduria type 8 (Orphanet:505208), Young-onset Parkinson disease (Orphanet:2828), Leigh syndrome (Orphanet:506)

HPO phenotypes

70 total (30 of 70 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000518	Cataract
HP:0000551	Color vision defect
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000952	Jaundice
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001643	Patent ductus arteriosus
HP:0001662	Bradycardia
HP:0001875	Decreased total neutrophil count
HP:0001998	Neonatal hypoglycemia

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C565204	Parkinson Disease 13 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523137 (SINGLE PROTEIN)

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 11 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.28	IC50	5200	nM	CHEMBL5277138
5.27	IC50	5400	nM	CHEMBL5286341
5.11	IC50	7800	nM	CHEMBL5274566
5.09	IC50	8100	nM	CHEMBL5284442
5.08	IC50	8300	nM	CHEMBL5278663
5.02	IC50	9500	nM	CHEMBL4583184

PubChem BioAssay actives

5 with measured affinity, of 20 total; 5 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-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-3-cyclopropyl-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	5.2000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	5.4000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	7.8000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4,4-dimethyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	8.1000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-3-cyclopropyl-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	8.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	affects cotreatment, affects localization, decreases localization, increases expression, increases reaction	5
Valproic Acid	affects expression, increases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Cannabidiol	affects cotreatment, decreases expression	2
Paraquat	decreases reaction, increases transport, affects localization	2
Tobacco Smoke Pollution	affects expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
moringin	affects cotreatment, decreases expression	1
tempol	affects cotreatment, affects localization, decreases reaction	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
trichostatin A	affects cotreatment, affects localization	1
cinnamaldehyde	affects localization, decreases reaction	1
beta-lapachone	decreases expression	1
lonidamine	affects cotreatment, affects localization	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
dinophysistoxin 1	increases expression	1
acetovanillone	affects cotreatment, affects localization, decreases reaction	1
oren gedoku to	affects localization, decreases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
alvocidib	affects localization	1
5,6-dichlorobenzimidazole	affects localization, increases reaction	1
bisphenol B	increases expression	1
UCF 101	affects cotreatment, affects localization, decreases reaction	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4482652	Binding	Inhibition of Omi/HtrA2 (unknown origin)-induced caspase-independent apoptosis in caspase 9 (-/-) fibroblasts transfected with Omi-GFP up to 10 uM incubated for 36 hrs by propidium iodide and 4’,6-diamidino-2-phenylindole staining based flu	Method and compounds for inhibition of cell death

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 1 transformed cell line, 1 stromal cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D9GI	Ubigene HEK293 HTRA2 KO	Transformed cell line	Female
CVCL_E1ZM	HAP1 HTRA2 (-) 2	Cancer cell line	Male
CVCL_E1ZN	HAP1 HTRA2 (-) 3	Cancer cell line	Male
CVCL_E1ZP	HAP1 HTRA2 (-) 4	Cancer cell line	Male
CVCL_RG44	MS-5-Omi/HTRA2-mCherry	Stromal cell line	Male
CVCL_XP64	HAP1 HTRA2 (-) 1	Cancer cell line	Male
CVCL_YT00	CIBi007-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism