HESX1

Summary

HESX1 (HESX homeobox 1, HGNC:4877) is a protein-coding gene on chromosome 3p14.3, encoding Homeobox expressed in ES cells 1 (Q9UBX0). Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland.

This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency.

Source: NCBI Gene 8820 — RefSeq curated summary.

At a glance

• Gene–disease (curated): septooptic dysplasia (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 140 total — 15 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 135
• Transcription factor: yes — 33 downstream targets (CollecTRI)
• MANE Select transcript: NM_003865

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4877
Approved symbol	HESX1
Name	HESX homeobox 1
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	RPX, ANF
Ensembl gene	ENSG00000163666
Ensembl biotype	protein_coding
OMIM	601802
Entrez	8820

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000295934, ENST00000473921, ENST00000495160, ENST00000647958, ENST00000918124

RefSeq mRNA: 5 — MANE Select: NM_003865 NM_001376058, NM_001376059, NM_001376060, NM_001376061, NM_003865

CCDS: CCDS2881

Canonical transcript exons

ENST00000295934 — 4 exons

Exon	Start	End
ENSE00001077062	57198391	57198492
ENSE00001077063	57199762	57199978
ENSE00001077064	57198753	57198952
ENSE00003836589	57197838	57198295

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 92.89.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8145 / max 145.7498, expressed in 542 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42644	1.0595	89
42643	0.8905	84
42645	0.8646	442

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.04	gold quality
right testis	UBERON:0004534	73.56	gold quality
left testis	UBERON:0004533	72.80	gold quality
testis	UBERON:0000473	71.62	gold quality
ventricular zone	UBERON:0003053	69.34	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	69.16	gold quality
right lobe of liver	UBERON:0001114	69.09	gold quality
right adrenal gland	UBERON:0001233	67.89	gold quality
right adrenal gland cortex	UBERON:0035827	67.84	gold quality
monocyte	CL:0000576	67.75	gold quality
left adrenal gland	UBERON:0001234	67.66	gold quality
mononuclear cell	CL:0000842	67.58	gold quality
left adrenal gland cortex	UBERON:0035825	67.40	gold quality
leukocyte	CL:0000738	67.32	gold quality
body of pancreas	UBERON:0001150	66.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	66.83	gold quality
spinal cord	UBERON:0002240	66.26	gold quality
adrenal cortex	UBERON:0001235	65.83	gold quality
adrenal tissue	UBERON:0018303	65.75	gold quality
gall bladder	UBERON:0002110	65.52	gold quality
adrenal gland	UBERON:0002369	65.51	gold quality
skin of leg	UBERON:0001511	65.09	gold quality
body of stomach	UBERON:0001161	65.07	gold quality
skin of abdomen	UBERON:0001416	64.39	gold quality
right coronary artery	UBERON:0001625	64.26	gold quality
pancreas	UBERON:0001264	64.24	gold quality
metanephros cortex	UBERON:0010533	64.19	gold quality
left ovary	UBERON:0002119	63.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6524	yes	280.31
E-ANND-3	no	3.48

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

33 targets.

Target	Regulation
ADAM2
CALM1
CAMK2A
CGA	Repression
CYP26A1
DHX9
ESR1
FSHB
GNRH1
HBA1
HESX1
KRAS
LHB
MAPK1
MMP2
MYH6
MYH7
MYL2
MYOCD
NCOR1
NLRP3
NPPA
NPPB
PKN1
POU1F1	Repression
PROP1
RCAN1
RHO
RLF
SAP30

JASPAR motifs

Motif	Name	Family
MA0894.1	HESX1	Paired-related HD factors
MA0894.2	HESX1	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:11748154

Upstream regulators (CollecTRI, top): HESX1, LHX1, LHX3, LMX1B, NCOR1, OTX2, POU1F1, PROP1, ZIC3

Literature-anchored findings (GeneRIF, showing 25)

• HESX1 mutations in septo-optic dysplasia will lead to a detailed understanding of its function in the development of the forebrain and pituitary–review (PMID:12424431)
• Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. The insertion of a heterozygous mutation (306/307ins AG) in the exon 2 of the HESX1. (PMID:12519827)
• novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding causing repression of PROP1 gene activity (PMID:14557462)
• “HESX1, a paired-like homeotic gene, has recently been reported to be defective in two siblings with septo-optic dysplasia(SOD)” p. 278 (PMID:14646405)
• “Mutations within HESX1 have been described in association with both dominant and recessive forms of septo-optic dysplasia, combined pituitary hormone deficiency and isolated growth hormone deficiency” p. 207 (PMID:14714741)
• index cases with autosomal-dominant isolated growth hormone deficiency and normal GH-1 gene had no HESX-1 mutations (PMID:16424673)
• Two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities. (PMID:16940453)
• Mutations within HESX1 are a rare cause of septooptic dysplasia and hypopituitarism (PMID:17148560)
• mutations in the key developmental gene HESX1 in patients with septo-optic dysplasia and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition (PMID:17587179)
• establish a link between HESX1 and DNMT1 and suggest a novel mechanism for the repressing properties of HESX1 (PMID:17931718)
• A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression in combined pituittary hormone deficiency. (PMID:18728160)
• Despite the significant influence of pairs 19/30 and 31/42 on the stability of the HESX1, their effect on DNA binding was modest. (PMID:19561080)
• Studies suggest that TLE1 and TLE3 might also play roles independent of HESX1 by interacting with other transcription factors like PROP1. (PMID:20181723)
• Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic growth hormone defiency, combined pituitary hormone deficiency and septo-optic dysplasia. (PMID:20694410)
• A large cohort of patients with schizencephaly, some with features of septo-optic dysplasia, were sequenced for mutations in LHX2, HESX1 and SOX2. (PMID:20949537)
• A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial Pituitary stalk interruption syndrome. (PMID:21270112)
• A c.357+3G>A mutation prevents the generation of one of the alternative isoforms normally produced by the wild-type allele, predicting a truncated HESX1 protein. (PMID:21325470)
• Data show no mutations in HESX1, PROP1, and POU1F1 genes, seven different mutations in CTNNB1 in 8/16 patients, and hyperexpression of miR-150. (PMID:21761366)
• Data indicate that HESX1, LHX4 and SOX3 polymorphisms may be associated with pituitary stalk interruption syndrome (PSIS). (PMID:23199197)
• expand the phenotypic spectrum of HESX1 mutations in Kallman syndrome. (PMID:23465708)
• investigated the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey (PMID:25500790)
• A novel heterozygous mutation in the HESX1 gene and a novel homozygous mutation in the PROP1 gene were detected in 2 pedigrees with combined pituitary hormone deficiency (PMID:26111865)
• HESX1 mutations cause variable clinical features in congenital hypopituitarism patients, which suggests an influence of modifier genes or environmental factors on the phenotype (PMID:27000987)
• Study did not identify HESX1 and LHX3 mutations by Sanger in brazilian patients with combined pituitary hormone deficiency (PMID:28734020)
• Homozygous HESX1 and COL1A1 Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis. (PMID:33451138)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hesx1	ENSMUSG00000040726
rattus_norvegicus	Hesx1	ENSRNOG00000014133

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox expressed in ES cells 1 — Q9UBX0 (reviewed: Q9UBX0)

Alternative names: Homeobox protein ANF

All UniProt accessions (3): C9J0A9, Q9UBX0, J3KR67

UniProt curated annotations — full annotation on UniProt →

Function. Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland. Possible transcriptional repressor. Binds to the palindromic PIII sequence, 5’-AGCTTGAGTCTAATTGAATTAACTGTAC-3’. HESX1 and PROP1 bind as heterodimers on this palindromic site, and, in vitro, HESX1 can antagonize PROP1 activation.

Subunit / interactions. Can form heterodimers with PROP1 in binding to DNA. Interacts with TLE1.

Subcellular location. Nucleus.

Disease relevance. Septooptic dysplasia (SOD) [MIM:182230] A clinically heterogeneous disorder defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia with panhypopopituitarism, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum. The disease is caused by variants affecting the gene represented in this entry. Growth hormone deficiency with pituitary anomalies (GHDPA) [MIM:182230] A disease characterized by low or absent growth hormone levels, in the presence of a hypoplastic anterior pituitary lobe and ectopic or absent posterior pituitary lobe. The disease is caused by variants affecting the gene represented in this entry. Pituitary hormone deficiency, combined, 5 (CPHD5) [MIM:182230] Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD5 is characterized by complete or partial deficiencies of growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ANF homeobox family.

RefSeq proteins (5): NP_001362987, NP_001362988, NP_001362989, NP_001362990, NP_003856* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR043402	Hesx1	Family

Pfam: PF00046

UniProt features (13 total): sequence variant 8, helix 3, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2K40	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBX0-F1	73.06	0.29

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 463 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_FOREBRAIN_MORPHOGENESIS, NKX25_02, GCANCTGNY_MYOD_Q6, GOBP_OTIC_VESICLE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_CADMIUM_ION, GOBP_GROWTH, GOBP_PITUITARY_GLAND_DEVELOPMENT, FOXO4_01, LHX3_01, FOXO1_01, CHX10_01

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), gonad development (GO:0008406), gene expression (GO:0010467), stem cell population maintenance (GO:0019827), pituitary gland development (GO:0021983), thyroid gland development (GO:0030878), otic vesicle formation (GO:0030916), multicellular organism growth (GO:0035264), camera-type eye development (GO:0043010), nose development (GO:0043584), regulation of embryonic development (GO:0045995), forebrain morphogenesis (GO:0048853), leukemia inhibitory factor signaling pathway (GO:0048861), stem cell differentiation (GO:0048863), canonical Wnt signaling pathway (GO:0060070), ERK1 and ERK2 cascade (GO:0070371), cellular response to cadmium ion (GO:0071276), regulation of DNA-templated transcription (GO:0006355), signal transduction (GO:0007165), Wnt signaling pathway (GO:0016055), forebrain development (GO:0030900), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (10): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), chromatin binding (GO:0003682), protein homodimerization activity (GO:0042803), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
animal organ development	2
multicellular organismal process	2
endocrine system development	2
gland development	2
binding	2
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
central nervous system development	1
head development	1
development of primary sexual characteristics	1
reproductive structure development	1
macromolecule biosynthetic process	1
maintenance of cell number	1
diencephalon development	1
otic vesicle morphogenesis	1
epithelial tube formation	1
developmental growth	1
eye development	1
sensory organ development	1
respiratory system development	1
embryo development	1
regulation of multicellular organismal development	1
anatomical structure morphogenesis	1
forebrain development	1
brain morphogenesis	1
enzyme-linked receptor protein signaling pathway	1
cell differentiation	1
Wnt signaling pathway	1
MAPK cascade	1
response to cadmium ion	1
cellular response to metal ion	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription cis-regulatory region binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1

Protein interactions and networks

STRING

832 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HESX1	POU1F1	P28069	949
HESX1	SOX3	P35714	769
HESX1	SOX2	P48431	726
HESX1	PROKR2	Q8NFJ6	699
HESX1	PRL	P01236	647
HESX1	GHRHR	Q02643	621
HESX1	NCOR1	O75376	610
HESX1	TLE1	Q04724	607
HESX1	TBX19	O60806	606
HESX1	TRH	P20396	592
HESX1	NKX2-1	P43699	578
HESX1	SIX3	O95343	566
HESX1	POU5F1	P31359	556
HESX1	ANOS1	P23352	555
HESX1	NANOG	Q9H9S0	551

IntAct

39 interactions, top by confidence:

A	B	Type	Score
HESX1	RBP4	psi-mi:“MI:0915”(physical association)	0.560
GUCD1	HESX1	psi-mi:“MI:0915”(physical association)	0.560
AIRIM	HESX1	psi-mi:“MI:0915”(physical association)	0.560
CATIP	HESX1	psi-mi:“MI:0915”(physical association)	0.560
UBL5	HESX1	psi-mi:“MI:0915”(physical association)	0.560
HOXC8	HESX1	psi-mi:“MI:0915”(physical association)	0.560
HESX1		psi-mi:“MI:0915”(physical association)	0.560
HESX1	RBP4	psi-mi:“MI:0914”(association)	0.560
KDM1A	HESX1	psi-mi:“MI:0915”(physical association)	0.510
HESX1	PRMT6	psi-mi:“MI:0915”(physical association)	0.510
HESX1	KDM1A	psi-mi:“MI:0915”(physical association)	0.510
HESX1	STAT3	psi-mi:“MI:0915”(physical association)	0.490
STAT3	HESX1	psi-mi:“MI:0915”(physical association)	0.490
HESX1		psi-mi:“MI:0915”(physical association)	0.370
	HESX1	psi-mi:“MI:0915”(physical association)	0.370
NPAS2	HESX1	psi-mi:“MI:0915”(physical association)	0.370
GUCD1	HESX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): HESX1 (Two-hybrid), RBP4 (Affinity Capture-MS), HESX1 (Two-hybrid), HESX1 (Two-hybrid), HESX1 (Two-hybrid), HESX1 (Two-hybrid), UBL5 (Two-hybrid), CBLN4 (Affinity Capture-MS), RBP4 (Affinity Capture-MS), HESX1 (Two-hybrid), NCOR1 (Reconstituted Complex), TLE1 (Affinity Capture-Western), TLE1 (Reconstituted Complex), KDM1A (Affinity Capture-Luminescence), PRMT6 (Affinity Capture-Luminescence)

ESM2 similar proteins: A1YGA2, A2T777, A5YC49, O42173, O42201, O42358, O42502, O42567, O93528, O93590, O97670, P09015, P31272, P35993, P42583, P52729, P52730, P53544, P79775, Q01703, Q01704, Q03356, Q03357, Q0P031, Q0P4H6, Q15699, Q1KKU7, Q28ET4, Q28J15, Q2PYN8, Q503F2, Q61658, Q804R0, Q804S6, Q8JJ26, Q91617, Q91898, Q91926, Q91975, Q98924

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	6
Uncertain significance	73
Likely benign	22
Benign	5

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1405989	NM_003865.3(HESX1):c.173del (p.Leu58fs)	Pathogenic
1470869	NM_003865.3(HESX1):c.135G>A (p.Trp45Ter)	Pathogenic
2061888	NM_003865.3(HESX1):c.389del (p.Asn130fs)	Pathogenic
2094701	NM_003865.3(HESX1):c.241G>T (p.Glu81Ter)	Pathogenic
2163319	NM_003865.3(HESX1):c.305_306del (p.Glu102fs)	Pathogenic
2294972	NM_003865.3(HESX1):c.254C>A (p.Ser85Ter)	Pathogenic
2579991	NM_003865.3(HESX1):c.99del (p.Asp34fs)	Pathogenic
492848	NM_003865.3(HESX1):c.240del (p.Glu81fs)	Pathogenic
7691	NM_003865.3(HESX1):c.478C>T (p.Arg160Cys)	Pathogenic
7694	NM_003865.3(HESX1):c.305_306dup (p.Leu103fs)	Pathogenic
7695	NM_003865.3(HESX1):c.77T>C (p.Ile26Thr)	Pathogenic
7696	NM_003865.3(HESX1):c.525del (p.Asn178fs)	Pathogenic
7697	NM_003865.3(HESX1):c.450_451del (p.Asp150fs)	Pathogenic
7698	NM_003865.3(HESX1):c.357+2T>C	Pathogenic
871254	NM_003865.3(HESX1):c.325C>T (p.Arg109Ter)	Pathogenic
1191108	NM_003865.3(HESX1):c.357+1G>A	Likely pathogenic
4294353	NM_003865.3(HESX1):c.48del (p.Ser17fs)	Likely pathogenic
4845672	NM_003865.3(HESX1):c.533del (p.Asn178fs)	Likely pathogenic
492849	NM_003865.3(HESX1):c.308T>A (p.Leu103Ter)	Likely pathogenic
503919	NM_003865.3(HESX1):c.106_107del (p.Val36fs)	Likely pathogenic
537760	NM_003865.3(HESX1):c.158-1G>C	Likely pathogenic

SpliceAI

202 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57198386:ATTAC:A	donor_loss	1.0000
3:57198387:TTACC:T	donor_loss	1.0000
3:57198388:TACC:T	donor_loss	1.0000
3:57198389:A:T	donor_loss	1.0000
3:57198390:CCTG:C	donor_loss	1.0000
3:57198489:CAAT:C	acceptor_gain	1.0000
3:57198493:C:CC	acceptor_gain	1.0000
3:57199758:ATACC:A	donor_loss	1.0000
3:57199759:TA:T	donor_loss	1.0000
3:57199760:ACC:A	donor_loss	1.0000
3:57198291:CAAAT:C	acceptor_gain	0.9900
3:57198293:AATC:A	acceptor_loss	0.9900
3:57198295:TC:T	acceptor_loss	0.9900
3:57198296:C:CC	acceptor_gain	0.9900
3:57198296:C:CG	acceptor_loss	0.9900
3:57198297:T:A	acceptor_loss	0.9900
3:57198404:T:TA	donor_gain	0.9900
3:57198491:ATC:A	acceptor_loss	0.9900
3:57198492:TCTAA:T	acceptor_loss	0.9900
3:57198493:CT:C	acceptor_loss	0.9900
3:57199756:GCATA:G	donor_loss	0.9900
3:57199757:CATA:C	donor_loss	0.9900
3:57199760:A:AC	donor_gain	0.9900
3:57199761:C:CC	donor_gain	0.9900
3:57198803:A:C	donor_gain	0.9800
3:57198491:ATCT:A	acceptor_gain	0.9700
3:57198748:C:A	donor_gain	0.9700
3:57198292:AAAT:A	acceptor_gain	0.9600
3:57198384:AAATT:A	donor_loss	0.9500
3:57198385:AATTA:A	donor_loss	0.9500

AlphaMissense

1207 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57198277:G:T	R160S	0.999
3:57198279:C:G	R159P	0.999
3:57198283:T:C	N158D	0.999
3:57198287:A:C	F156L	0.999
3:57198287:A:T	F156L	0.999
3:57198288:A:G	F156S	0.999
3:57198289:A:G	F156L	0.999
3:57198292:A:G	W155R	0.999
3:57198292:A:T	W155R	0.999
3:57198469:A:C	F127L	0.999
3:57198469:A:T	F127L	0.999
3:57198471:A:G	F127L	0.999
3:57198482:A:G	L123S	0.999
3:57198765:A:C	F115L	0.999
3:57198765:A:T	F115L	0.999
3:57198767:A:G	F115L	0.999
3:57198281:A:C	N158K	0.998
3:57198281:A:T	N158K	0.998
3:57198282:T:C	N158S	0.998
3:57198282:T:G	N158T	0.998
3:57198290:C:A	W155C	0.998
3:57198290:C:G	W155C	0.998
3:57198425:G:T	A142D	0.998
3:57198436:T:A	R138S	0.998
3:57198436:T:G	R138S	0.998
3:57198766:A:C	F115C	0.998
3:57198766:A:G	F115S	0.998
3:57198284:T:A	Q157H	0.997
3:57198284:T:G	Q157H	0.997
3:57198288:A:C	F156C	0.997

dbSNP variants (sampled 300 via entrez): RS1000095921 (3:57210611 T>C), RS1000105810 (3:57220223 G>A), RS1000123158 (3:57210945 G>A), RS1000182501 (3:57226609 T>C), RS1000216672 (3:57200238 G>A), RS1000227102 (3:57228728 A>G), RS1000248669 (3:57219124 CCT>C), RS1000434830 (3:57219392 G>A), RS1000552180 (3:57226001 G>A,T), RS1000783269 (3:57198304 A>C), RS1000845814 (3:57206640 C>T), RS1000887609 (3:57205530 C>T), RS1000920484 (3:57205837 T>G), RS1000949116 (3:57211951 G>A), RS1001024440 (3:57220745 A>C,G,T)

Disease associations

OMIM: gene MIM:601802 | disease phenotypes: MIM:182230, MIM:613038

GenCC curated gene-disease

Disease	Classification	Inheritance
septooptic dysplasia	Strong	Autosomal dominant
combined pituitary hormone deficiencies, genetic form	Strong	Autosomal dominant
hypothyroidism due to deficient transcription factors involved in pituitary development or function	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant
pituitary stalk interruption syndrome	Supportive	Autosomal dominant

Mondo (7): septooptic dysplasia (MONDO:0008428), pituitary hormone deficiency, combined, 1 (MONDO:0024464), combined pituitary hormone deficiencies, genetic form (MONDO:0013099), amenorrhea (MONDO:0001836), hypothyroidism due to deficient transcription factors involved in pituitary development or function (MONDO:0016411), Kallmann syndrome (MONDO:0018800), pituitary stalk interruption syndrome (MONDO:0019828)

Orphanet (3): Septo-optic dysplasia spectrum (Orphanet:3157), Combined pituitary hormone deficiencies, genetic forms (Orphanet:95494), Male infertility with spermatogenesis disorder (Orphanet:399775)

HPO phenotypes

135 total (30 of 135 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000141	Amenorrhea
HP:0000144	Decreased fertility
HP:0000158	Macroglossia
HP:0000175	Cleft palate
HP:0000270	Delayed cranial suture closure
HP:0000282	Facial edema
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000458	Anosmia
HP:0000470	Short neck
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007320_56	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-08
GCST007321_23	Family history of Alzheimer’s disease	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009268	family history of Alzheimer’s disease

MeSH disease descriptors (4)

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
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500
C567803	Pituitary Hormone Deficiency, Combined, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
trichostatin A	affects expression, affects cotreatment, decreases expression	4
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
methylmercuric chloride	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Estradiol	decreases expression	1
Silicon Dioxide	decreases expression	1
Teratogens	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1
p-Chloromercuribenzoic Acid	decreases expression	1
Particulate Matter	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2P0	SEES3-1V human HESX1, clone1	Embryonic stem cell	Male
CVCL_A2P1	SEES3-1V human HESX1, clone2	Embryonic stem cell	Male
CVCL_A2P2	SEES3-1V human HESX1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
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)
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
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00064987	PHASE2	TERMINATED	Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism
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
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)
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
NCT05717855	Not specified	COMPLETED	Screening of Septo-optic Dysplasia During a Fetal Examination at 16-20 Weeks of Gestation
NCT06262152	Not specified	UNKNOWN	Sleep Profile of Patients With Septo-optic Dysplasia
NCT00392457	Not specified	COMPLETED	Investigating the Regulation of Reproductive Hormones in Adult Men
NCT00494169	Not specified	COMPLETED	Investigation of the Genetic Causes of Kallmann Syndrome and Reproductive Disorders
NCT00623116	Not specified	UNKNOWN	A Study to Characterize Epidemiology, Clinical and Genetic Features of Kallmann Syndrome in Finland
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT01914172	Not specified	COMPLETED	Health Needs of Patients With Kallmann Syndrome
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04733274	Not specified	ACTIVE_NOT_RECRUITING	Patient and Healthcare Professional Views on Genetic/Genomic Information and Testing
NCT05971836	Not specified	ACTIVE_NOT_RECRUITING	The Molecular Basis of Inherited Reproductive Disorders
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
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