SOHLH2

Summary

SOHLH2 (spermatogenesis and oogenesis specific basic helix-loop-helix 2, HGNC:26026) is a protein-coding gene on chromosome 13q13.3, encoding Spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein 2 (Q9NX45). Transcription regulator of both male and female germline differentiation.

This gene encodes one of testis-specific transcription factors which are essential for spermatogenesis, oogenesis and folliculogenesis. This gene is located on chromosome 13. The proteins encoded by this gene and another testis-specific transcription factor, SOHLH1, can form heterodimers, in addition to homodimers. There is a read-through locus (GeneID: 100526761) that shares sequence identity with this gene and the upstream CCDC169 (GeneID: 728591). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54937 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited primary ovarian failure (Limited, GenCC)
• GWAS associations: 3
• MANE Select transcript: NM_017826

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26026
Approved symbol	SOHLH2
Name	spermatogenesis and oogenesis specific basic helix-loop-helix 2
Location	13q13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20449, TEB1, bHLHe81, SPATA28
Ensembl gene	ENSG00000120669
Ensembl biotype	protein_coding
OMIM	616066
Entrez	54937

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000317764, ENST00000379881

RefSeq mRNA: 2 — MANE Select: NM_017826 NM_001282147, NM_017826

CCDS: CCDS61309, CCDS9355

Canonical transcript exons

ENST00000379881 — 11 exons

Exon	Start	End
ENSE00001482811	36168217	36169054
ENSE00001860914	36214479	36214556
ENSE00003468475	36174476	36174567
ENSE00003545937	36173692	36173810
ENSE00003575063	36191795	36191894
ENSE00003581191	36170531	36170787
ENSE00003589590	36201879	36202093
ENSE00003591714	36174722	36174869
ENSE00003595139	36193621	36193725
ENSE00003633069	36193806	36193867
ENSE00003637676	36189946	36190056

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 99.61.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4755 / max 125.2234, expressed in 66 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136775	0.4407	64
136776	0.0348	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.61	gold quality
oocyte	CL:0000023	99.50	gold quality
sperm	CL:0000019	94.64	gold quality
male germ cell	CL:0000015	91.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.36	gold quality
left testis	UBERON:0004533	82.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.72	gold quality
right testis	UBERON:0004534	81.68	gold quality
testis	UBERON:0000473	81.56	gold quality
cortical plate	UBERON:0005343	73.19	gold quality
adult organism	UBERON:0007023	71.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	63.62	gold quality
placenta	UBERON:0001987	60.52	gold quality
nucleus accumbens	UBERON:0001882	60.27	gold quality
prefrontal cortex	UBERON:0000451	59.40	gold quality
smooth muscle tissue	UBERON:0001135	58.85	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.33	gold quality
primary visual cortex	UBERON:0002436	58.31	gold quality
anterior cingulate cortex	UBERON:0009835	58.31	gold quality
cingulate cortex	UBERON:0003027	58.27	gold quality
corpus epididymis	UBERON:0004359	57.61	gold quality
hypothalamus	UBERON:0001898	57.42	gold quality
right adrenal gland	UBERON:0001233	57.22	gold quality
seminal vesicle	UBERON:0000998	56.75	silver quality
Brodmann (1909) area 23	UBERON:0013554	56.24	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	56.22	gold quality
cauda epididymis	UBERON:0004360	56.11	silver quality
neocortex	UBERON:0001950	55.87	gold quality
urinary bladder	UBERON:0001255	55.60	gold quality
right frontal lobe	UBERON:0002810	55.45	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ENAD-17	no	182.20
E-ANND-3	no	2.29

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CXCL8	Activation
KIT	Activation

JASPAR motifs

Motif	Name	Family
MA1560.1	SOHLH2	PAS domain factors
MA1560.2	SOHLH2	PAS domain factors

JASPAR matrix evidence (PMIDs): PMID:26869299

miRNA regulators (miRDB)

46 targeting SOHLH2, 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-432-3P	100.00	67.86	705
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-143-3P	99.49	69.05	1457

Literature-anchored findings (GeneRIF, showing 12)

• Our identification of novel variants in the SOHLH2 gene, in women with POF of both Chinese and Serbian origin, strongly suggests an important role for SOHLH2 in human POF etiology. (PMID:24524832)
• Low Sohlh2 expression is associated with ovarian cancer. (PMID:24858206)
• The polymorphisms rs1328626 and rs6563386 of the SOHLH2 gene would be the genetic risk factors for nonobstructive azoospermia in the Chinese population. The SNP rs1328641 might influence testes development in the NOA patients. (PMID:25463635)
• Results identified MMP9 as a novel target for transcriptional inactivation by Sohlh2 and demonstrated that the Sohlh2 downregulation of MMP9 is critical for inhibiting human ovarian cancer cell invasion. (PMID:26153894)
• the expression of Sohlh genes in human tissues (PMID:26375665)
• sohlh2 functions as a tumor metastasis suppressor via suppressing IL-8 expression in breast cancer (PMID:27384482)
• Data found that sohlh2 overexpression inhibited breast cancer cell proliferation in vitro and tumor growth in vivo. In contrast, sohlh2 silencing induced the opposite effects. These functional effects of sohlh2 were exerted through inhibiting Wnt/beta- catenin signaling by the increase of APC expression. These findings provide a novel mechanistic role of sohlh2 in breast tumorigenesis. (PMID:30720232)
• Sohlh2 alleviates malignancy of EOC cells under hypoxia via inhibiting the HIF1alpha/CA9 signaling pathway. (PMID:31318683)
• Intronic variation of the SOHLH2 gene confers risk to male reproductive impairment. (PMID:32690270)
• Germline variants at SOHLH2 influence multiple myeloma risk. (PMID:33875642)
• SOHLH2 Suppresses Angiogenesis by Downregulating HIF1alpha Expression in Breast Cancer. (PMID:34158392)
• Sohlh2 Regulates the Stemness and Differentiation of Colon Cancer Stem Cells by Downregulating LncRNA-H19 Transcription. (PMID:36287177)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sohlh2	ENSMUSG00000027794
rattus_norvegicus	Sohlh2	ENSRNOG00000038091

Paralogs (1): SOHLH1 (ENSG00000165643)

Protein

Protein identifiers

Spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein 2 — Q9NX45 (reviewed: Q9NX45)

All UniProt accessions (1): Q9NX45

UniProt curated annotations — full annotation on UniProt →

Function. Transcription regulator of both male and female germline differentiation. Suppresses genes involved in spermatogonial stem cells maintenance, and induces genes important for spermatogonial differentiation. Coordinates oocyte differentiation without affecting meiosis I.

Subunit / interactions. Forms both hetero- and homodimers with SOHLH1.

Subcellular location. Nucleus. Cytoplasm.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NX45-1	1	yes
Q9NX45-2	2
Q9NX45-3	3

RefSeq proteins (2): NP_001269076, NP_060296* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR039583	TCFL5/SOLH1/2	Family

Pfam: PF00010

UniProt features (10 total): splice variant 3, sequence conflict 3, sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX45-F1	58.36	0.11

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 91 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, NKX25_02, GCANCTGNY_MYOD_Q6, GOBP_OOGENESIS, GOBP_MALE_GAMETE_GENERATION, HATADA_METHYLATED_IN_LUNG_CANCER_DN, chr13q13, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, LIAO_METASTASIS, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_OOCYTE_DIFFERENTIATION, NKX22_01, GOBP_FEMALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, FREAC7_01

GO Biological Process (6): regulation of transcription by RNA polymerase II (GO:0006357), spermatogenesis (GO:0007283), oocyte differentiation (GO:0009994), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355), oogenesis (GO:0048477)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein dimerization activity (GO:0046983)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
developmental process involved in reproduction	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
protein dimerization activity	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
male gamete generation	1
cell differentiation	1
oogenesis	1
cellular developmental process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
germ cell development	1
female gamete generation	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
identical protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
protein binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOHLH2	SOHLH1	Q5JUK2	919
SOHLH2	NOBOX	O60393	748
SOHLH2	FIGLA	Q6QHK4	734
SOHLH2	STRA8	Q7Z7C7	684
SOHLH2	NANOS2	P60321	684
SOHLH2	LHX8	Q68G74	682
SOHLH2	DAZL	Q92904	657
SOHLH2	GFRA1	P56159	603
SOHLH2	NANOS3	P60323	597
SOHLH2	DMRT1	Q9Y5R6	597
SOHLH2	ZBTB16	Q05516	594
SOHLH2	SYCP3	Q8IZU3	565
SOHLH2	GDF9	O60383	556
SOHLH2	TERT	O14746	550
SOHLH2	RPA3	P35244	545

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ELOA2	SOHLH2	psi-mi:“MI:0915”(physical association)	0.370
MAPT	LANCL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (1): SOHLH2 (Two-hybrid)

ESM2 similar proteins: A0JMR6, A1A4L6, A1YG61, A2T737, O70273, O75747, P01105, P10157, P11308, P13474, P14921, P15036, P15037, P15062, P18755, P19102, P26323, P27577, P41156, P41157, P41212, P57782, P81270, P97360, Q08AW4, Q15052, Q32LN0, Q3SZL0, Q3US16, Q58DT0, Q60641, Q6GPJ8, Q6P3D7, Q7ZYI3, Q8BZ05, Q8C7R7, Q8HWS3, Q8N8B7, Q8NDB2, Q8VDK3

Diamond homologs: Q3MHT3, Q6IUP1, Q9D489, Q9NX45

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SOHLH2	“up-regulates quantity by expression”	KIT	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1459 predictions. Top by Δscore:

Variant	Effect	Δscore
13:36170788:C:CC	acceptor_gain	1.0000
13:36173812:T:C	acceptor_gain	1.0000
13:36174882:T:TC	acceptor_gain	1.0000
13:36190052:CAGAG:C	acceptor_gain	1.0000
13:36191890:CTTAA:C	acceptor_gain	1.0000
13:36191895:C:CC	acceptor_gain	1.0000
13:36201873:GTTTA:G	donor_loss	1.0000
13:36201877:ACC:A	donor_loss	1.0000
13:36202089:TTTGC:T	acceptor_gain	1.0000
13:36202090:TTGC:T	acceptor_gain	1.0000
13:36202091:TGC:T	acceptor_gain	1.0000
13:36202092:GC:G	acceptor_gain	1.0000
13:36202093:CC:C	acceptor_gain	1.0000
13:36202093:CCTGA:C	acceptor_loss	1.0000
13:36202094:C:CC	acceptor_gain	1.0000
13:36202095:T:C	acceptor_loss	1.0000
13:36214473:TCTTA:T	donor_loss	1.0000
13:36214474:CTTAC:C	donor_loss	1.0000
13:36214475:TTA:T	donor_loss	1.0000
13:36214476:TA:T	donor_loss	1.0000
13:36214478:C:CA	donor_loss	1.0000
13:36214478:CCTGG:C	donor_gain	1.0000
13:36170789:T:C	acceptor_gain	0.9900
13:36170790:T:C	acceptor_gain	0.9900
13:36173810:CCT:C	acceptor_gain	0.9900
13:36173812:T:TC	acceptor_gain	0.9900
13:36173971:T:TA	donor_gain	0.9900
13:36174449:T:TA	donor_gain	0.9900
13:36174475:CCG:C	donor_gain	0.9900
13:36174882:T:C	acceptor_gain	0.9900

AlphaMissense

2767 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:36174869:C:A	R214S	0.994
13:36174869:C:G	R214S	0.994
13:36189948:T:A	R213S	0.991
13:36189948:T:G	R213S	0.991
13:36174781:C:G	A244P	0.990
13:36174840:A:G	L224P	0.990
13:36189946:C:G	R214T	0.988
13:36174795:G:T	A239D	0.987
13:36189949:C:G	R213T	0.987
13:36174800:A:C	D237E	0.986
13:36174800:A:T	D237E	0.986
13:36174801:T:C	D237G	0.985
13:36189946:C:A	R214M	0.985
13:36174801:T:G	D237A	0.984
13:36174802:C:G	D237H	0.984
13:36174837:C:G	R225P	0.984
13:36174801:T:A	D237V	0.982
13:36174786:A:T	L242H	0.978
13:36174786:A:G	L242P	0.975
13:36189960:C:A	K209N	0.975
13:36189960:C:G	K209N	0.975
13:36174861:A:G	I217T	0.974
13:36174863:T:A	R216S	0.974
13:36174863:T:G	R216S	0.974
13:36174535:A:C	F274L	0.972
13:36174535:A:T	F274L	0.972
13:36174537:A:G	F274L	0.972
13:36174793:A:G	S240P	0.972
13:36189957:T:A	E210D	0.972
13:36189957:T:G	E210D	0.972

dbSNP variants (sampled 300 via entrez): RS1000031280 (13:36211420 G>A), RS1000074576 (13:36216412 G>T), RS1000112672 (13:36178601 G>A,C), RS1000205408 (13:36183662 T>C), RS1000224269 (13:36191208 TGA>T,TGAGA), RS1000276524 (13:36190946 A>G), RS1000429308 (13:36190934 T>C), RS1000524051 (13:36215614 G>A), RS1000597442 (13:36169868 C>T), RS1000605261 (13:36192258 C>T), RS1000633320 (13:36209510 A>C), RS1000666988 (13:36176499 A>G), RS1000698092 (13:36176976 G>C,T), RS1000829294 (13:36168991 C>T), RS1000840908 (13:36196832 C>T)

Disease associations

OMIM: gene MIM:616066 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited primary ovarian failure	Limited	Autosomal dominant

Mondo (1): inherited primary ovarian failure (MONDO:0019852)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001519_17	Economic and political preferences	6.000000e-06
GCST002726_51	Glucose homeostasis traits	4.000000e-07
GCST008399_20	Cocaine dependence	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004827	economic and social preference
EFO:0006832	disposition index measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
Aflatoxin B1	affects expression, increases methylation	2
methylmercuric chloride	increases expression	1
trichostatin A	increases expression, decreases expression	1
3,4-dichloroaniline	decreases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
incobotulinumtoxinA	decreases expression	1
Rosiglitazone	increases expression	1
Decitabine	increases expression	1
Diuron	decreases expression	1
Silver	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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