SRA1

Summary

SRA1 (steroid receptor RNA activator 1, HGNC:11281) is a protein-coding gene on chromosome 5q31.3, encoding Steroid receptor RNA activator 1 (Q9HD15). Functional RNA which acts as a transcriptional coactivator that selectively enhances steroid receptor-mediated transactivation ligand-independently through a mechanism involving the modulating N-terminal domain (AF-1) of steroid receptors.

Both long non-coding and protein-coding RNAs are transcribed from this gene, and they represent alternatively spliced transcript variants. This gene was initially defined as a non-coding RNA, which is a coactivator for several nuclear receptors (NRs) and is associated with breast cancer. It has now been found that this gene is involved in the regulation of many NR and non-NR activities, including metabolism, adipogenesis and chromatin organization. The long non-coding RNA transcripts interact with a variety of proteins, including the protein encoded by this gene. The encoded protein acts as a transcriptional repressor by binding to the non-coding RNA.

Source: NCBI Gene 10011 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 112 total
• Phenotypes (HPO): 12
• MANE Select transcript: NM_001035235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11281
Approved symbol	SRA1
Name	steroid receptor RNA activator 1
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	SRA, STRAA1
Ensembl gene	ENSG00000213523
Ensembl biotype	protein_coding
OMIM	603819
Entrez	10011

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000336283, ENST00000520427, ENST00000523259, ENST00000602657, ENST00000602775, ENST00000602875, ENST00000919851, ENST00000919852, ENST00000919853, ENST00000955074

RefSeq mRNA: 2 — MANE Select: NM_001035235 NM_001035235, NM_001253764

CCDS: CCDS34245

Canonical transcript exons

ENST00000336283 — 5 exons

Exon	Start	End
ENSE00001162502	140557147	140557272
ENSE00001350365	140557428	140557473
ENSE00003483748	140551982	140552184
ENSE00003579818	140550068	140550911
ENSE00003665343	140551061	140551169

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8250 / max 204.6326, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63796	28.6895	1819
63794	0.1355	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	97.80	gold quality
left adrenal gland	UBERON:0001234	95.07	gold quality
left adrenal gland cortex	UBERON:0035825	95.06	gold quality
right adrenal gland	UBERON:0001233	95.02	gold quality
right adrenal gland cortex	UBERON:0035827	94.84	gold quality
adrenal cortex	UBERON:0001235	94.82	gold quality
adenohypophysis	UBERON:0002196	94.23	gold quality
left ventricle myocardium	UBERON:0006566	94.08	silver quality
cardiac muscle of right atrium	UBERON:0003379	93.92	silver quality
adrenal gland	UBERON:0002369	93.89	gold quality
stromal cell of endometrium	CL:0002255	93.07	gold quality
blood	UBERON:0000178	93.06	gold quality
granulocyte	CL:0000094	92.96	gold quality
pituitary gland	UBERON:0000007	92.93	gold quality
gastrocnemius	UBERON:0001388	92.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.30	gold quality
body of stomach	UBERON:0001161	92.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.06	gold quality
muscle of leg	UBERON:0001383	92.03	gold quality
cerebellar hemisphere	UBERON:0002245	92.01	gold quality
cerebellar cortex	UBERON:0002129	91.90	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.71	gold quality
right lobe of liver	UBERON:0001114	91.64	gold quality
right testis	UBERON:0004534	91.55	gold quality
monocyte	CL:0000576	91.54	gold quality
leukocyte	CL:0000738	91.54	gold quality
tibialis anterior	UBERON:0001385	91.47	silver quality
parotid gland	UBERON:0001831	91.41	gold quality
apex of heart	UBERON:0002098	91.35	gold quality
nasal cavity epithelium	UBERON:0005384	91.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.89
E-GEOD-93593	yes	8.83

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ESR1, ESR2, NCOA1, NCOA2, NCOA3, POU5F1, RORA, THRA

miRNA regulators (miRDB)

35 targeting SRA1, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-4797-3P	97.48	67.14	989
HSA-MIR-4286	97.20	64.37	1587

Literature-anchored findings (GeneRIF, showing 40)

• Reduction of coactivator expression by antisense oligodeoxynucleotides inhibits ERalpha transcriptional activity and MCF-7 proliferation (PMID:11818499)
• Results identify three new steroid receptor RNA activator (SRA-RNA) isoforms that likely encode stable proteins, and that are widely expressed in breast cancer cell lines. (PMID:12565891)
• 2.0A crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif (PMID:12909012)
• SRA potentiates the estrogen-induced transcriptional activity of both ERalpha and ERbeta. (PMID:12943696)
• SRA is an ERalpha AF-1-specific coactivator that enhances the agonist activity of tamoxifen-bound ERalpha and may contribute to tamoxifen resistance (PMID:15351741)
• Upregulation of steroid receptor RNA activator is associated with serous Cystadenocarcinoma of the ovary (PMID:15607539)
• data suggest that the presence of both coding SRA RNA and its corresponding SRAP modifies the activity of estrogen receptor in breast cancer cells and that SRAP could be a new clinical marker for breast cancer (PMID:16152589)
• analysis of of a complex formed by the SRC1 interaction domain (SID) of CBP and the activation domain (AD1) of SRC1 (PMID:16540468)
• Alternative splicing of intron-1 is used by breast cancer cells to regulate the balance between coding and functional noncoding SRA1 RNA. (PMID:16848684)
• alternative splicing of intron-1 is one mechanism used by breast cancer cells to regulate the balance between coding and functional noncoding SRA1 RNAs (PMID:16848684)
• STAT3, Runx2, and steroid receptor coactivator-1 are critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF (thoracic ossification of ligament flavum) (PMID:17702747)
• At least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. (PMID:19064678)
• These findings reveal novel functions of SRA and Dax-1 in steroidogenesis and adrenal biology. (PMID:19188450)
• A significant (Student’s t-test, P < 0.003) higher SRA-intron-1 relative expression is reported in breast tumors with higher progesterone receptor contents. (PMID:19483093)
• in breast cancer patients, SRAP levels were higher in estrogen receptor-alpha positive, in progesterone receptor positive & in older patients; data suggest SRAP levels may provide additional information on prognosis in a specific set of patients (PMID:19740422)
• Chlamydial protease CT441 interacts with SRAP1 co-activator of estrogen receptor alpha and partially alleviates its co-activation activity. (PMID:20079837)
• Both transcript and protein products of the SRA1 gene co-modulate the transcriptional activity of steroid receptors. (PMID:20153324)
• The data suggest unanticipated roles for SRA in glucose uptake, cellular signaling, T(3) hormone generation, and invasion/metastasis. (PMID:20219889)
• SRA noncoding RNA enhances myogenic differentiation and myogenic conversion of non-muscle cells through the co-activation of MyoD activity, but SRAP prevented this SRA RNA-dependant co-activation. (PMID:20855289)
• DEAD-box RNA helicase p68 (DDX5) and its associated noncoding RNA, steroid receptor RNA activator (SRA), form a complex with CTCF that is essential for insulator function (PMID:20966046)
• A report of the first experimentally derived secondary structure of a human lncRNA, the steroid receptor RNA activator. (PMID:22362738)
• results show that the NTD of ERalpha and AR contains a novel RBM that directly binds SRA, and that STR5 can serve as a novel class of RNA inhibitor of ERalpha and AR signaling by interfering with Pus1p-mediated SRA pseudouridylation (PMID:22998747)
• This study provides evidence that both ER-beta1 and SRAP could be predictive biomarkers of tamoxifen benefit in ER-alpha-negative premenopausal early breast cancer. (PMID:23579816)
• In endometrioma patients, the surrounding ovarian tissue steroid receptor RNA activator expression is higher compared to controls. (PMID:23749764)
• The presence of SRAP and multiple SRAP-like peptides in estrogen receptor positive breast cancer samples correlates with clinical outcome. (PMID:23907597)
• The structure is a five-helix bundle that is distinct from known RNA-binding motifs and instead is similar to the carboxy-terminal domain of the yeast spliceosome protein PRP18, which stabilizes specific protein-protein interactions. (PMID:24486609)
• NMR spectra of SRA1p in the presence of its 80-nt RNA target indicate that this protein must be part of a multi-protein complex in order to recognize its proposed RNA recognition element. (PMID:24486611)
• lncRNA SRA expression is potentially associated with PCOS and it has positive correlation with obesity in PCOS, thereby suggesting that elevated lncRNA SRA might be an important mediator in adiposity-related processes in PCOS for susceptible individuals. (PMID:25609053)
• in human pluripotent stem cells SRA interacts with NANOG and is important for maintenance of the pluripotent state. (PMID:26496121)
• Data suggest that expression of SRA1 (mRNA and protein) is linked to cancer cell motility (invasiveness of breast/cervical tumor cells) and regulation of gene expression. (PMID:26581859)
• These findings suggest that SRA genetic variants may contribute to breast cancer risk (PMID:26967566)
• By studying a cohort of idiopathic hypogonadotropic hypogonadism, our findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans (PMID:27086651)
• REVIEW: Biologic function and role in disease (PMID:27282881)
• Results identified H15-H18 domains in SRA gene playing a key role in regulating ER-mediated transcription. (PMID:27406387)
• Steroid receptor RNA activator 1-small interfering RNA treatment significantly increased ER-alpha levels but reduced ER-beta levels in endometriotic stromal cells (ESCs). (PMID:27694140)
• SRA1 was down expressed in HCC and its level was associated with tumor size and GLU level in patients with HCC for the first time. SRA1 may be a helpful biomarker to diagnostic HCC. (PMID:28085012)
• our findings demonstrated that lncRNA SRA is highly correlated with cancer progression and cervical cancer cell proliferation and migration. Furthermore, these results indicate that lncRNA SRA may be a potential therapeutic target and prognostic marker for cervical malignancy. (PMID:29039612)
• long noncoding RNA steroid receptor RNA activator 1 played an antitumor role in osteosarcoma as it reduced cell migration, invasion, and proliferation, but facilitated cell apoptosis via sponging microRNA-208a, which could be regarded as a potential therapeutic target of osteosarcoma treatment. (PMID:31106680)
• Steroid receptor RNA activator affects the development of poststroke depression by regulating the peroxisome proliferator-activated receptor gamma signaling pathway. (PMID:31714481)
• Association between long-chain non-coding RNA SRA1 gene single-nucleotide polymorphism and polycystic ovary syndrome susceptibility. (PMID:32783135)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sra1	ENSDARG00000053619
mus_musculus	Sra1	ENSMUSG00000006050
rattus_norvegicus	Sra1	ENSRNOG00000018089

Protein

Protein identifiers

Steroid receptor RNA activator 1 — Q9HD15 (reviewed: Q9HD15)

Alternative names: Steroid receptor RNA activator protein

All UniProt accessions (2): Q9HD15, R4GMW4

UniProt curated annotations — full annotation on UniProt →

Function. Functional RNA which acts as a transcriptional coactivator that selectively enhances steroid receptor-mediated transactivation ligand-independently through a mechanism involving the modulating N-terminal domain (AF-1) of steroid receptors. Also mediates transcriptional coactivation of steroid receptors ligand-dependently through the steroid-binding domain (AF-2). Enhances cellular proliferation and differentiation and promotes apoptosis in vivo. May play a role in tumorigenesis.

Subunit / interactions. SRA1 RNA exists in a ribonucleoprotein complex containing NCOA1. The RNA also forms a complex with PUS1 and RARG in the nucleus. Interacts with AR.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Highly expressed in liver and skeletal muscle and to a lesser extent in brain. Also expressed in both normal and tumorigenic breast epithelial cell lines. Significantly up-regulated in human tumors of the breast, ovary, and uterus.

Miscellaneous. Appears to be the first example of a new class of functional RNAs also able to encode a protein.

Similarity. Belongs to the SRA1 family.

RefSeq proteins (2): NP_001030312, NP_001240693 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009917	SRA1/Sec31	Domain
IPR040243	Steroid_recept_RNA_1	Family

Pfam: PF07304

UniProt features (20 total): helix 5, turn 3, modified residue 3, region of interest 2, sequence conflict 2, compositionally biased region 2, chain 1, strand 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4NBO	X-RAY DIFFRACTION	2.81
2MGX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HD15-F1	77.23	0.45

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 (3): 48, 57, 75

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 136 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, WANG_LMO4_TARGETS_DN, GROSS_HYPOXIA_VIA_HIF1A_ONLY, GOBP_NEGATIVE_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MYOBLAST_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, chr5q31, GOCC_RIBONUCLEOPROTEIN_COMPLEX, GOMF_SINGLE_STRANDED_RNA_BINDING, BENPORATH_ES_1, GOMF_TRANSCRIPTION_COACTIVATOR_ACTIVITY, PID_ERA_GENOMIC_PATHWAY, BIOCARTA_PPARA_PATHWAY

GO Biological Process (4): apoptotic process (GO:0006915), negative regulation of myoblast differentiation (GO:0045662), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (3): steroid receptor RNA activator RNA binding (GO:0002153), transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), intercellular bridge (GO:0045171)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
myoblast differentiation	1
negative regulation of cell differentiation	1
regulation of myoblast differentiation	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
single-stranded RNA binding	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1

Protein interactions and networks

STRING

514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SRA1	RARG	P13631	818
SRA1	DDX5	P17844	794
SRA1	DDX17	Q92841	790
SRA1	DMBT1	Q9UGM3	767
SRA1	NCOA1	Q15788	691
SRA1	SLIRP	Q9GZT3	637
SRA1	ESR1	P03372	603
SRA1	PUS1	Q9Y606	593
SRA1	MYOD1	P15172	480
SRA1	KLF4	P78338	473
SRA1	NCOR1	O75376	450
SRA1	OXCT1	P55809	445
SRA1	AR	P10275	439
SRA1	SCARB1	Q8WTV0	433
SRA1	NCOR2	Q9Y618	408

IntAct

16 interactions, top by confidence:

A	B	Type	Score
OAZ1	AZIN1	psi-mi:“MI:0914”(association)	0.640
HDAC2	SRA1	psi-mi:“MI:0915”(physical association)	0.590
SRA1	HDAC2	psi-mi:“MI:0915”(physical association)	0.590
Ercc6l	RPL17	psi-mi:“MI:0914”(association)	0.350
RUFY1	PKN2	psi-mi:“MI:0914”(association)	0.350
TIGD6	ZRANB2	psi-mi:“MI:0914”(association)	0.350
SAP30	BRMS1	psi-mi:“MI:0914”(association)	0.350
MLKL	CASP8	psi-mi:“MI:0914”(association)	0.350
Mib1	TBC1D31	psi-mi:“MI:0914”(association)	0.350
POLK	TIA1	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
SRA1	SEC24D	psi-mi:“MI:0914”(association)	0.350
RAET1L	ENDOD1	psi-mi:“MI:0914”(association)	0.350
CEP43	RIPK2	psi-mi:“MI:2364”(proximity)	0.270
SRA1	UBE2Z	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (77): SRA1 (Co-fractionation), SRA1 (Proximity Label-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), SRA1 (Reconstituted Complex), SRA1 (Affinity Capture-Western), SRA1 (Affinity Capture-MS), SEC24D (Affinity Capture-MS)

ESM2 similar proteins: A0M8T5, A1A4L4, B0UYH6, B9EJA2, E1C213, Q00PJ1, Q07E15, Q07E28, Q09YG9, Q09YI1, Q09YK4, Q09YM8, Q12789, Q13625, Q17R10, Q2IBA2, Q2IBB2, Q2IBD4, Q2IBF7, Q2QL82, Q2QLA2, Q2QLB3, Q2QLF8, Q4G0A6, Q5DTU0, Q5I0E6, Q5R4C9, Q5R789, Q5RF72, Q5RJ80, Q6NZY4, Q6P1H6, Q6QGW5, Q7TP65, Q80U93, Q80VJ2, Q86XL3, Q8BFU3, Q8CG79, Q8N4X5

Diamond homologs: A1C6X5, A1DHK2, A2QBZ0, A3GFK8, A4RD35, A5DTX3, I7MM07, O13637, O94979, Q0CYG9, Q0ULF5, Q1DX43, Q2GVT8, Q2UF60, Q3UPL0, Q4P2B6, Q4X0M4, Q5AZM3, Q5F3X8, Q5R4F4, Q5S580, Q6BRR2, Q6C414, Q6FNU4, Q6QGW5, Q7SYD5, Q873A1, Q9HD15, Q9Z2Q1, A5DB75, Q55CT5, Q5AAU3, Q80VJ2, Q75A30

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	20
Benign	18

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1516 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140550831:A:G	W194R	0.999
5:140550831:A:T	W194R	0.999
5:140557253:C:A	W27C	0.999
5:140557253:C:G	W27C	0.999
5:140557255:A:G	W27R	0.999
5:140557255:A:T	W27R	0.999
5:140550863:A:G	L183P	0.998
5:140550814:T:A	K199N	0.997
5:140550814:T:G	K199N	0.997
5:140550815:T:A	K199I	0.996
5:140550829:C:A	W194C	0.996
5:140550829:C:G	W194C	0.996
5:140550863:A:T	L183H	0.996
5:140550869:C:G	R181P	0.996
5:140550873:G:C	H180D	0.996
5:140550818:A:T	V198D	0.995
5:140551142:G:T	R140S	0.995
5:140550809:A:G	L201S	0.994
5:140550816:T:C	K199E	0.994
5:140550857:A:T	V185D	0.994
5:140551102:A:G	L153S	0.994
5:140557248:T:C	D29G	0.994
5:140550822:C:G	G197R	0.993
5:140550822:C:T	G197R	0.993
5:140550827:A:C	M195R	0.993
5:140550821:C:T	G197E	0.992
5:140550827:A:T	M195K	0.992
5:140557254:C:G	W27S	0.992
5:140550851:T:G	H187P	0.991
5:140550863:A:C	L183R	0.991

dbSNP variants (sampled 300 via entrez): RS1000935895 (5:140558375 G>A), RS1001155927 (5:140552213 A>G), RS1002166066 (5:140557698 T>A,C,G), RS1002250498 (5:140558440 T>G), RS1002382269 (5:140558017 C>T), RS1002884312 (5:140555000 T>C), RS1003258643 (5:140559733 C>T), RS1003431456 (5:140557036 C>T), RS1004441675 (5:140551533 G>A), RS1004946474 (5:140556640 G>A), RS1005099325 (5:140549614 T>C), RS1005132265 (5:140556208 T>A), RS1005193166 (5:140558893 G>A), RS1005412262 (5:140559235 C>T), RS1005581426 (5:140552926 G>A)

Disease associations

OMIM: gene MIM:603819 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): amenorrhea (MONDO:0001836), Kallmann syndrome (MONDO:0018800)

Orphanet (1): Kallmann syndrome (Orphanet:478)

HPO phenotypes

12 total (13 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0003621	Juvenile onset
HP:0004408	Abnormality of the sense of smell
HP:0008734	Decreased testicular size
HP:0000141	Amenorrhea

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004946_157	Schizophrenia	2.000000e-08
GCST010002_39	Refractive error	2.000000e-14
GCST010146_22	Serum immune biomarker levels	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004872	inflammatory biomarker measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	2
Estradiol	increases reaction, decreases expression, affects binding	2
Nickel	increases expression	2
Aflatoxin B1	increases expression	2
GSK-J4	decreases expression	1
1,1-bis(4-hydroxyphenyl)-2,2-dichloroethylene	affects binding, decreases reaction	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
sodium arsenite	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
cylindrospermopsin	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Vehicle Emissions	decreases expression, decreases reaction	1
Cisplatin	increases expression	1
Diuron	decreases expression	1
Doxorubicin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Tretinoin	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, decreases reaction	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00064987	PHASE2	TERMINATED	Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT00392756	PHASE1	COMPLETED	Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS)
NCT00493961	PHASE1	COMPLETED	Studying the Effects of 7 Days of Gonadotropin Releasing Hormone (GnRH) Treatment in Men With Hypogonadism
NCT00914823	PHASE1	COMPLETED	Kisspeptin Administration in the Adult
NCT01438034	PHASE1	COMPLETED	Kisspeptin in the Evaluation of Delayed Puberty
NCT03118479	PHASE1	TERMINATED	Effect of Varying Testosterone Levels on Insulin Sensitivity in Men With Idiopathic Hypogonadotropic Hypogonadism (IHH)
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women
NCT00556400	PHASE1/PHASE2	TERMINATED	Treatment of Menorrhagia in Women With Thrombocytopenia Using Platelets or Platelets and Hormones
NCT01187043	PHASE1/PHASE2	COMPLETED	Determination of the Lowest, Safe and Effective Dose of Proellex
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00011388	Not specified	COMPLETED	Reproductive Effects of Pesticide, PCB and Mercury Exposure in Laotian Immigrants
NCT00243607	Not specified	COMPLETED	Hydrotherapy Against Menopausal Symptoms in Breast Cancer Survivors
NCT00260286	Not specified	COMPLETED	Effects of Gynecological Age on LH Sensitivity to Energy Availability
NCT00456274	Not specified	UNKNOWN	Baselines in Reproductive Disorders
NCT00589654	Not specified	ACTIVE_NOT_RECRUITING	Menstrual Cycle Maintenance and Quality of Life: A Prospective Study
NCT01423487	Not specified	WITHDRAWN	Efficacy and Safety of Metformin in Preventing Patients With Risperidone From Weight Gain and Amenorrhea
NCT01500447	Not specified	RECRUITING	Inherited Reproductive Disorders
NCT01511588	Not specified	COMPLETED	Hormonal Regulation of Puberty and Fertility
NCT01785719	Not specified	COMPLETED	Evaluation of Ovarian Morphology and Function in Overweight Women During Weight Loss
NCT01927432	Not specified	COMPLETED	Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
NCT02224976	Not specified	COMPLETED	Effect of Intense Training on Ovarian Function and Bone Turnover
NCT04135729	Not specified	COMPLETED	Mental Health in Fitness Instructors
NCT04424576	Not specified	RECRUITING	Ovarian Morphology in Girls
NCT04938622	Not specified	COMPLETED	Bioenergetics of Exercise-Induced Menstrual Disturbances
NCT06280807	Not specified	RECRUITING	Observation of Environment and Reproductive-Endocrine Effects
NCT06800170	Not specified	RECRUITING	Treatment of Menstrual Cycle Alterations in Adolescents