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SOHLH2 (spermatogenesis and oogenesis specific basic helix-loop-helix 2)

Written2019-03Flavia R Mangone, Ana Carolina Pavanelli, Maria A. Nagai
Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of So Paulo; Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of So Paulo, Av. Dr. Arnaldo, 251, CEP 01296-000, So Paulo, Brazil.

Abstract Review on SOHLH2, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords SOHLH2; Cell Differentiation; Spermatogenesis; Oogenesis; Folliculogenesis; Azoospermia; Premature Ovarian Failure; Epithelial Ovarian Cancer; Breast Cancer

(Note : for Links provided by Atlas : click)


Alias (NCBI)EB1
HGNC Alias symbFLJ20449
HGNC Alias namespermatogenesis associated 28
LocusID (NCBI) 54937
Atlas_Id 55087
Location 13q13.3  [Link to chromosome band 13q13]
Location_base_pair Starts at 36168217 and ends at 36214556 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SOHLH2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Note Readthrough gene: CCDC169-SOHLH2 (Gene ID: 100526761). This locus represents naturally occurring read-through transcription between the neighboring CCDC169 (C13orf38 chromosome 13 open reading frame 38) and SOHLH2 (spermatogenesis and oogenesis specific basic helix-loop-helix 2) genes. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each gene. [provided by RefSeq, Nov 2010] .
Description DNA size: 46,408 bp (NG_033786.1); mRNA size: 2125 bp (NM_017826.3); 11 exons.
SOHLH2 was mapped to human chromosome 13q13 and consist of 46,408 base pairs, starting at base pair 36,168,208 and ending at base pair 36,214,615 according to last released (GRCh38/hg38).
This gene encodes one of the 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. [provided by RefSeq, Aug 2013].
It has been described that the promoter region of SOHLH2 gene includes a CpG island, and SOHLH2 promoter hypomethylation was detected in 44% of 61 cancer cell lines and 30% of the primary tumours representing the major tumour types (Shen et al., 2007).
Transcription Two transcript variants encoding different isoforms have been found for this gene.
NM_017826.3 spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein 2 isoform 1: Protein (NP_060296.2) - 425 aa; mRNA (NM_017826.3) - 2125 bp; Description: This variant (1) represents the longer transcript and encodes the longer isoform (2).
NM_001282147.1 spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein 2 isoform 2: Protein (NP_001269076.1) - 225 aa; mRNA (NM_001282147.1) - 1936 bp corresponding to 7 exons (Ensembl); Description: This variant lacks several exons but has an alternate 3' terminal exon, compared to variant 1. The resulting isoform is much shorter and has a distinct C-terminus, compared to isoform 1.


Note Molecular weight: NP_060296.2 ~46.9 kDa, 425aa; NP_001269076.1 ~25.1 kDa, 225 aa
  Figure 1 - Schematic representation of the human SOHLH2 protein SOHLH2 is a 425aa protein with one basic helix-loop-helix DNA-binding motif (bHLH, 197-257aa)
Description SOHLH2 is a ~46.9 kDa protein (initially described as a 51kDa (Ballow et al., 2006)), composed of 425 amino acids, with an isoelectric point of 7.1377. SOHLH2 has a basic helix-loop-helix DNA-binding (bHLH) motif of 60aa (197-257aa) thus it has being described as a transcription factor (figure 1). The amino-terminal portion of bHLH corresponds to the basic domain, enabling the binding of the protein to its consensus sequence at the DNA, known as E-Box. The HLH portion is at the carboxy-terminal portion of bHLH and is a structure covering two α -helices connected by a loop which is responsible for the interactions with other protein subunits to form homo- and heterodimeric complexes (Jones, 2004; Gyoja, 2017).
Expression SOHLH2 protein expression is observed in the nuclei of oocytes, and weak staining is present in the cytoplasm of theca cells and granular cells in the ovary. The SOHLH2 transcripts expression are detectable specifically in the oocytes of small follicles of female embryonic gonad. In adult ovaries, SOHLH2 protein is present in primordial follicles and absent in growing oocytes (Ballow et al., 2006). In testis, SOHLH2 is found mainly in spermatogonia and Sertoli cells in seminiferous tubule and Leydig cells outside of seminiferous tubules (Ballow et al., 2006; Zhang et al., 2015). Although SOHLH2 has been initially described in testis and oocytes, it is widely expressed in normal adult human tissues. The expression of SOHLH2 is also observed in the cytoplasm of the three kinds of muscle tissues: skeletal, cardiac and smooth. SOHLH2 protein expression was also found in other tissues derived from embryonic mesoderm such as kidney and uterine tube (Zhang et al., 2015). In neurons, Sohlh2 were detected mainly in the nuclei, while it was not detectable by IHC in neuroglial cells. The expression of SOHLH2 gene was also detected in some other tissues derived from embryonic ectoderm including iris, ciliary body, and retina (Zhang et al., 2015).
Localisation SOHLH2 is an intracellular protein present predominantly in the nucleus but also in the cytoplasm of specific cell types (Zhang et al., 2015; Shin et al., 2017). Its translocation from the cytoplasm is associated with expression of SOHLH1 (Shin et al., 2017).
Function Tissue-specific basic helix-loop-helix (bHLH) transcription factors play critical roles in cell differentiation
SOHLH2 is described as a transcription regulator of both male and female germline differentiation. SOHLH2, together with SOHLH1, regulates oocyte growth and differentiation (Shin et al., 2017). SOHLH proteins modulate the expression of genes involved in spermatogonial stem cells maintenance (SSC), such as RET, GFRA1, NANOS2, and POU5F1. Also, it regulates the expression of genes essential for spermatogonial differentiation such as KIT, and SOX3 (Suzuki et al., 2012).
According to Toyoda et al. SOHLH2 forms a ternary complex with SOHLH1, and SP1 and cooperatively regulates the transcription of SOHLH1 gene (Toyoda et al., 2014).
  Figure 2 - Schematic representation of the mechanism of action of SOHLH2. SOHLH2 negatively regulates cell proliferation trough upregulation of APC expression and inhibition of Wnt/βcatenin signaling and suppresses migration and invasion by down-regulation of IL-8. SOHLH2 - spermatogenesis and oogenesis specific basic helix-loop-helix 2; APC - adenomatosis polyposis coli/APC regulator of WNT signaling pathway; IL-8 - Interleukin 8 (Zhang et al., 2016; Ji et al, 2016)
Homology Although SOHLH2 was identified as a homologue of SOHLH1, their limited homology is confined to the bHLH domains (~50%) (Suzuki et al., 2012). The bHLH protein domain of SOHLH2 is the most conserved region among different species (Ballow et al., 2006). The described identity among mouse SOHLH2 protein with the rat and human orthologue is 84% and 50%, respectively (Ballow et al., 2006).

Implicated in

Note SOHLH2 is a transcription regulator involved in spermatogenesis and oogenesis, but also in Cancer: Basic helix-loop-helix (bHLH) proteins play several roles in tumorigenesis, such as cell differentiation, cell cycle arrest and apoptosis (Sun et al., 2007).
Entity Spermatogenesis and Azoospermia
Note Spermatogenesis is a process by which male gametes, known as sperm, are formed from primordial germ cells (spermatogonia).
Hao et al. (2008) have observed that mice null for Sohlh2 (Sohlh2 -/-) showed testis with a significantly diminished size. Moreover, based on testicular atrophy, functional studies have shown that type A spermatogonia differentiation was interrupted in SOHLH2 null mice (Hao et al., 2008).
Azoospermia is a condition characterized by the absence of sperm cells in the semen, classified into two groups: obstructive azoospermia (OA) and non-obstructive azoospermia (NOA). In a Chinese study evolving a cohort of 361 of patients, Song et al. have described two variants, with different risk impact of NOA development. The rs6563386 variant conferred a higher risk of NOA while the rs1328626 variant was associated with lower risk of NOA, suggesting a direct relation of SOHLH2 gene to NOA development (Song et al., 2015).
Entity Premature Ovarian Failure
Note The Premature Ovarian Failure (POF), sometimes referred to as Premature Menopause, is a human female gonadal failure before forty years old. Eleven variants of SOHLH2 were described in a series of 561 POF patients, suggesting that this gene might play a role in human POF etiology (Qin et al., 2014). In another work, the association of SOHLH2 with POF development was suggested after exposure of mice to common endocrine disrupting chemicals (EDCs) present in the environmental. These authors found that after exposure to EDCs, the SOHLH2 protein and mRNA were downregulated and as a consequence, these mice presented an impaired primordial follicular development (Tran et al., 2018).
Entity Epithelial Ovarian Cancer (EOC)
Note SOHLH2 seems to be related to EOC tumorigenesis. The SOHLH2 immunostaining was evaluated in tumors from 65 EOC patients, and it was observed that those with SOHLH2 negative tumors presented lower overall survival as compared to positive tumors. In vitro studies were conducted to assess the impact of SOHLH2 in the cellular growth of EOC derived cell lines and obtained data showed that SOHLH2 overexpression inhibited proliferation of HO8910 and OVCAR3 cells. In accordance with that, the injection of HO8910 overexpressing SOHLH2 in nude mice caused a lower tumor growth rate as compared to the control group. The mechanism involved in this reduced tumor growth seems to be associated with the induction of CDKN1A (also designated WAF1/CIP1 or "p21") and inhibition of CCND1 (cyclin D1) expression as observed in HO8910 overexpressing SOHLH2. These data suggest that SOHLH2 might act as a tumor suppressor in EOC (Zhang et al., 2014).
In another study, the SOHLH2 reduction expression was significantly associated with distant metastasis as compared to borderline ovarian tumors and EOC without metastasis. Taking all these into consideration, SOHLH2 seems to play a role in EOC tumorigenesis and invasion (Zhang et al., 2016).
Entity Breast Cancer
Note The overexpression of SOHLH2 in MDA-MB-231 cell line inhibited metastasis and epithelial-mesenchymal transition (EMT) by controlling transcription of CXCL8 (IL-8) through binding to its promoter region. On the other hands, SOHLH2 silence increased migration and invasion, suggesting that this protein may negatively regulate metastasis and play an important role in EMT (Ji et al., 2016).
Primary breast tumors express reduced levels of SOHLH2 in comparison with normal tissue (Zhang et al., 2019). Also, SOHLH2 expression is associated to cellular proliferation in vitro and tumor growth in vivo acting as a tumor suppressor gene. The tumor suppressor effects on breast cancer seem to occur due to SOHLH2 inhibition of WNT/β-catenin through the increase of APC (Zhang et al., 2019) (figure 2).
Previous data from our group have shown the association between SOHLH2 and triple negative breast cancer (TNBC). Patients with TNBC with reduced expression of SOHLH2 show shorter disease-free and a tendency to lower overall survival rates compared to patients with tumors with increased expression of SOHLH2, suggesting that SOHLH2 expression might be a potential candidate biomarker with potential prognostic value for TNBC. (De Alcantara Filho et al., 2018)


Sohlh2 is a germ cell-specific bHLH transcription factor
Ballow DJ, Xin Y, Choi Y, Pangas SA, Rajkovic A
Gene Expr Patterns 2006 Oct;6(8):1014-8
PMID 16765102
Basic helix-loop-helix transcription factors in evolution: Roles in development of mesoderm and neural tissues
Gyoja F
Genesis 2017 Sep;55(9)
PMID 28804953
Sohlh2 knockout mice are male-sterile because of degeneration of differentiating type A spermatogonia
Hao J, Yamamoto M, Richardson TE, Chapman KM, Denard BS, Hammer RE, Zhao GQ, Hamra FK
Stem Cells 2008 Jun;26(6):1587-97
PMID 18339773
Sohlh2 suppresses epithelial to mesenchymal transition in breast cancer via downregulation of IL-8
Ji S, Zhang W, Zhang X, Hao C, Hao A, Gao Q, Zhang H, Sun J, Hao J
Oncotarget 2016 Aug 2;7(31):49411-49424
PMID 27384482
An overview of the basic helix-loop-helix proteins
Jones S
Genome Biol 2004;5(6):226
PMID 15186484
Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure
Qin Y, Jiao X, Dalgleish R, Vujovic S, Li J, Simpson JL, Al-Azzawi F, Chen ZJ
Fertil Steril 2014 Apr;101(4):1104-1109
PMID 24524832
Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters
Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP
PLoS Genet 2007 Oct;3(10):2023-36
PMID 17967063
Transcription factors SOHLH1 and SOHLH2 coordinate oocyte differentiation without affecting meiosis I
Shin YH, Ren Y, Suzuki H, Golnoski KJ, Ahn HW, Mico V, Rajkovic A
J Clin Invest 2017 Jun 1;127(6):2106-2117
PMID 28504655
Association of genetic variants in SOHLH1 and SOHLH2 with non-obstructive azoospermia risk in the Chinese population
Song B, Zhang Y, He XJ, Du WD, Ruan J, Zhou FS, Wu H, Zha X, Xie XS, Ye L, Wei ZL, Zhou P, Cao YX
Eur J Obstet Gynecol Reprod Biol 2015 Jan;184:48-52
PMID 25463635
bHLH-Orange Transcription Factors in Development and Cancer
Sun H, Ghaffari S, Taneja R
Transl Oncogenomics 2007 Dec 10;2:107-20
PMID 23641148
SOHLH1 and SOHLH2 coordinate spermatogonial differentiation
Suzuki H, Ahn HW, Chu T, Bowden W, Gassei K, Orwig K, Rajkovic A
Dev Biol 2012 Jan 15;361(2):301-12
PMID 22056784
Auto-regulation of the Sohlh1 gene by the SOHLH2/SOHLH1/SP1 complex: implications for early spermatogenesis and oogenesis
Toyoda S, Yoshimura T, Mizuta J, Miyazaki J
PLoS One 2014 Jul 8;9(7):e101681
PMID 25003626
Depletion of follicles accelerated by combined exposure to phthalates and 4-vinylcyclohexene diepoxide, leading to premature ovarian failure in rats
Tran DN, Jung EM, Yoo YM, Ahn C, Kang HY, Choi KC, Hyun SH, Dang VH, Pham TN, Jeung EB
Reprod Toxicol 2018 Sep;80:60-67
PMID 29969652
Sohlh2 inhibits human ovarian cancer cell invasion and metastasis by transcriptional inactivation of MMP9
Zhang H, Hao C, Wang Y, Ji S, Zhang X, Zhang W, Zhao Q, Sun J, Hao J
Mol Carcinog 2016 Jul;55(7):1127-37
PMID 26153894
Sohlh2 inhibits ovarian cancer cell proliferation by upregulation of p21 and downregulation of cyclin D1
Zhang H, Zhang X, Ji S, Hao C, Mu Y, Sun J, Hao J
Carcinogenesis 2014 Aug;35(8):1863-71
PMID 24858206
Sohlh2 inhibits breast cancer cell proliferation by suppressing Wnt/β-catenin signaling pathway
Zhang X, Liu R, Zhao N, Ji S, Hao C, Cui W, Zhang R, Hao J
Mol Carcinog 2019 Feb 5
PMID 30720232


This paper should be referenced as such :
Flavia R Mangone, Ana Carolina Pavanelli, Maria A Nagai
SOHLH2 (spermatogenesis and oogenesis specific basic helix-loop-helix 2)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(2):54-57.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)SOHLH2   26026
Entrez_Gene (NCBI)SOHLH2    spermatogenesis and oogenesis specific basic helix-loop-helix 2
AliasesSOSF2; SPATA28; TEB1; bHLHe81
GeneCards (Weizmann)SOHLH2
Ensembl hg19 (Hinxton)ENSG00000120669 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000120669 [Gene_View]  ENSG00000120669 [Sequence]  chr13:36168217-36214556 [Contig_View]  SOHLH2 [Vega]
ICGC DataPortalENSG00000120669
Genatlas (Paris)SOHLH2
SOURCE (Princeton)SOHLH2
Genetics Home Reference (NIH)SOHLH2
Genomic and cartography
GoldenPath hg38 (UCSC)SOHLH2  -     chr13:36168217-36214556 -  13q13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SOHLH2  -     13q13.3   [Description]    (hg19-Feb_2009)
GoldenPathSOHLH2 - 13q13.3 [CytoView hg19]  SOHLH2 - 13q13.3 [CytoView hg38]
Genome Data Viewer NCBISOHLH2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AI368806 AK000456 AY884305 BC025383 DB022954
RefSeq transcript (Entrez)NM_001282147 NM_017826
Consensus coding sequences : CCDS (NCBI)SOHLH2
Gene ExpressionSOHLH2 [ NCBI-GEO ]   SOHLH2 [ EBI - ARRAY_EXPRESS ]   SOHLH2 [ SEEK ]   SOHLH2 [ MEM ]
Gene Expression Viewer (FireBrowse)SOHLH2 [ Firebrowse - Broad ]
GenevisibleExpression of SOHLH2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54937
GTEX Portal (Tissue expression)SOHLH2
Human Protein AtlasENSG00000120669-SOHLH2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NX45   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9NX45  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NX45
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)   
Domains : Interpro (EBI)bHLH_dom    HLH_DNA-bd_sf    SOHLH2   
Domain families : Pfam (Sanger)HLH (PF00010)   
Domain families : Pfam (NCBI)pfam00010   
Domain families : Smart (EMBL)HLH (SM00353)  
Conserved Domain (NCBI)SOHLH2
AlphaFold pdb e-kbQ9NX45   
Human Protein Atlas [tissue]ENSG00000120669-SOHLH2 [tissue]
Protein Interaction databases
IntAct (EBI)Q9NX45
Ontologies - Pathways
Ontology : AmiGOchromatin  RNA polymerase II cis-regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription factor activity, RNA polymerase II-specific  nucleus  cytoplasm  regulation of transcription by RNA polymerase II  multicellular organism development  spermatogenesis  oocyte differentiation  cell differentiation  cell differentiation  protein homodimerization activity  protein heterodimerization activity  sequence-specific double-stranded DNA binding  
Ontology : EGO-EBIchromatin  RNA polymerase II cis-regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription factor activity, RNA polymerase II-specific  nucleus  cytoplasm  regulation of transcription by RNA polymerase II  multicellular organism development  spermatogenesis  oocyte differentiation  cell differentiation  cell differentiation  protein homodimerization activity  protein heterodimerization activity  sequence-specific double-stranded DNA binding  
NDEx NetworkSOHLH2
Atlas of Cancer Signalling NetworkSOHLH2
Wikipedia pathwaysSOHLH2
Orthology - Evolution
GeneTree (enSembl)ENSG00000120669
Phylogenetic Trees/Animal Genes : TreeFamSOHLH2
Homologs : HomoloGeneSOHLH2
Homology/Alignments : Family Browser (UCSC)SOHLH2
Gene fusions - Rearrangements
Fusion : QuiverSOHLH2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSOHLH2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SOHLH2
Exome Variant ServerSOHLH2
GNOMAD BrowserENSG00000120669
Varsome BrowserSOHLH2
ACMGSOHLH2 variants
Genomic Variants (DGV)SOHLH2 [DGVbeta]
DECIPHERSOHLH2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSOHLH2 
ICGC Data PortalSOHLH2 
TCGA Data PortalSOHLH2 
Broad Tumor PortalSOHLH2
OASIS PortalSOHLH2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSOHLH2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSOHLH2
Mutations and Diseases : HGMDSOHLH2
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)SOHLH2
DoCM (Curated mutations)SOHLH2
CIViC (Clinical Interpretations of Variants in Cancer)SOHLH2
NCG (London)SOHLH2
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry SOHLH2
NextProtQ9NX45 [Medical]
Target ValidationSOHLH2
Huge Navigator SOHLH2 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDSOHLH2
Pharm GKB GenePA144596273
Clinical trialSOHLH2
DataMed IndexSOHLH2
PubMed23 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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