Alternative titles; symbols
HGNC Approved Gene Symbol: SOHLH1
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:135,693,407-135,702,112 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Ovarian dysgenesis 5 | 617690 | Autosomal recessive | 3 |
| Spermatogenic failure 32 | 618115 | Autosomal dominant | 3 |
SOHLH1 and SOHLH2 (616066) are key players in early folliculogenesis. They are also expressed during early testis development in undifferentiated spermatogonia and are important regulators of spermatogenesis (summary by Kumar, 2017).
Using an in silico subtraction strategy to identify genes preferentially expressed during early folliculogenesis, Pangas et al. (2006) identified mouse Sohlh1. The predicted 357-amino acid basic helix-loop-helix (bHLH) transcription factor shares 86% identity in the bHLH region with the human protein. RT-PCR analysis detected expression in mouse ovary and testis only. In embryos, expression was abundant in ovaries after embryonic day 15.5. Immunohistochemistry of adult mice showed nuclear and cytoplasmic expression of Sohlh1 protein in germ cell cysts, primordial follicles, and primary, but not secondary, follicles.
By Western blot and immunofluorescence microscopy, Shin et al. (2017) demonstrated that Sohlh2 was expressed in mouse germline as early as embryonic day 12.5 (E12.5), preceding Sohlh1 expression. Sohlh1 was detectable at E15.5, corresponding to translocation of Sohlh2 from cytoplasm to nucleus. Nobox (610934) and Lhx8 (604425), important regulators of postnatal oogenesis, were coexpressed with Sohlh1.
Stumpf (2017) mapped the SOHLH1 gene to chromosome 9q34.3 based on an alignment of the SOHLH1 sequence (Genbank BC031861) with the genomic sequence (GRCh38).
Suzuki et al. (2012) demonstrated coexpression of Sohlh1 and Sohlh2 in the majority of spermatogonia in adult mice, but not in Gfra1 (601496)-expressing spermatogonia. Coimmunoprecipitation analysis determined that Sohlh1 and Sohlh2 both hetero- and homodimerized.
Ovarian Dysgenesis 5
In 4 affected sisters from 2 unrelated consanguineous Turkish families with ovarian dysgenesis (ODG5; 617690), Bayram et al. (2015) identified homozygosity for either a 1-bp deletion (610224.0001) or a nonsense mutation (Y9X; 610224.0002) in the SOHLH1 gene. The mutations segregated with disease in each family and were not found in controls.
Spermatogenic Failure 32
Choi et al. (2010) analyzed the candidate gene SOHLH1 in 96 Korean men with nonobstructive azoospermia (SPGF32; 618115) and identified 2 patients who were heterozygous for a de novo splice site mutation (c.346-1G-A; 610224.0003). Two additional patients were heterozygous for missense variants in SOHLH1 (C31R or P177T); however, neither missense change was predicted to affect the 2-dimensional structure of the protein, and neither affected transcriptional activity in a transactivation assay.
Nakamura et al. (2017) analyzed 25 azoospermia-associated genes in 40 Japanese men with infertility due to nonobstructive azoospermia and identified the previously reported SOHLH1 c.346-1G-A splice site mutation in 2 patients.
Pangas et al. (2006) found that Sohlh1 -/- female mice, but not Sohlh1 +/- females, were infertile with atrophic ovaries that lacked oocytes. Immunohistochemical analysis of Sohlh1 -/- mice demonstrated normal expression of Gcna1, but expression of Msy2 (YBX2; 611447) occurred only in oocytes and putative primordial follicles, indicating a defect in follicle development. In situ hybridization and RT-PCR showed that Sohlh1 -/- ovaries expressed less Figla (608697) and Nobox (610934) than wildtype ovaries. Microarray and in situ hybridization indicated that Lhx8 (604425) was also drastically downregulated in Sohlh1 -/- ovaries. Pangas et al. (2006) proposed that LHX8 and NOBOX are candidate genes for direct regulation by SOHLH1 and that these genes, along with FIGLA, may be involved in nonsyndromic ovarian failure.
Suzuki et al. (2012) found that mice lacking Sohlh1 or Sohlh2 or both Sohlh1 and Sohlh2 were indistinguishable and that Sohlh1 and/or Sohlh2 deficiency did not affect spermatogonia survival and proliferation. Deficiency of Sohlh1 and/or Sohlh2 resulted in precocious commitment to meiosis in a subset of cells. Double deficiency of Sohlh1 and Sohlh2 had a synergistic effect on gene expression patterns compared with the single knockouts. Chromatin immunoprecipitation analysis showed that Sohlh1 and Sohlh2 bound chromatin upstream of genes essential for spermatogonial stem cell (SSC) maintenance and differentiation, including their own genes. Suzuki et al. (2012) concluded that SOHLH1 and SOHLH2 affect spermatogonia development by directly regulating GFRA1, SOX3 (313430), and KIT (164920) and that they suppress genes involved in SSC maintenance and induce genes important for spermatogonia differentiation.
Shin et al. (2017) found that deficiency of either Sohlh1 or Sohlh2 in mice disrupted expression of Nobox and Lhx8 in embryonic gonads without affecting meiosis. Sohlh1 -/- mice were infertile, and fertility could be restored by conditional expression of a Sohlh1 transgene after the onset of meiosis. Infertility of Sohlh2 -/- mice could not be rescued by Sohlh1 or Sohlh2 transgene expression due to a lack of expression of either in rescued mice. Shin et al. (2017) concluded that deficiency of these transcription factors disrupts embryonic expression of oocyte differentiation factors NOBOX and LHX8, without significant effects on meiosis stage I. They proposed that SOHLH1 and SOLH2 are regulators of both male and female germline differentiation, with distinct and sex-specific downstream pathways.
In 2 sisters from a consanguineous Turkish family (HOU1852) with ovarian dysgenesis (ODG5; 617690), Bayram et al. (2015) identified homozygosity for a 1-bp deletion (c.705delT, NM_001012415) in exon 6 of the SOHLH1 gene, causing a frameshift predicted to result in a premature termination codon (Pro235fsTer4). The mutation was present in heterozygosity in their unaffected parents, and was not found in more than 3,000 in-house exomes, including more than 700 persons of Turkish ancestry, in exome data from the Atherosclerosis Risk in Communities study, or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, dbSNP, or ExAC databases.
In 2 sisters from a consanguineous Turkish family (CF1374) with ovarian dysgenesis (ODG5; 617690), originally reported by Abaci et al. (2007), Bayram et al. (2015) identified homozygosity for a c.27C-G transversion (c.27C-G, NM_001012415) in exon 1 of the SOHLH1 gene, resulting in a tyr9-to-ter (Y9X) substitution. The mutation was present in heterozygosity in their unaffected parents, and was not found in more than 3,000 in-house exomes, including more than 700 persons of Turkish ancestry, in exome data from the Atherosclerosis Risk in Communities study, or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, dbSNP, or ExAC databases.
In 2 unrelated Korean men with nonobstructive azoospermia (SPGF32; 618115), Choi et al. (2010) identified heterozygosity for a de novo splice site mutation (c.346-1G-A, NM_001012415.1) in intron 3 of the SOHLH1 gene that was not found in their parents or in 159 Korean men with a normal sperm count. RT-PCR analysis of mRNA from transiently transfected HEK293T cells revealed mutant transcripts that were shorter than wildtype, and sequence analysis confirmed an in-frame deletion (18 bp) within exon 4, resulting in truncation of the bHLH domain. In transcriptional activity assays, the mutant protein showed less than half of the activity of wildtype protein.
Nakamura et al. (2017) analyzed 25 azoospermia-associated genes in 40 Japanese men with infertility due to nonobstructive azoospermia and identified the previously reported SOHLH1 c.346-1G-A splice site mutation in 2 patients.
Abaci, A., Bober, E., Unuvar, T., Atas, A., Buyukgebiz, A. Case report of two siblings with familal (sic) ovarian dysgenesis. Minerva Pediat. 59: 57-59, 2007. [PubMed: 17301727]
Bayram, Y., Gulsuner, S., Guran, T., Abaci, A., Yesil, G., Unal Gulsuner, H., Atay, Z., Pierce, S. B., Gambin, T., Lee, M., Turan, S., Bober, E., and 12 others. Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism. J. Clin. Endocr. Metab. 100: E808-E814, 2015. Note: Electronic Article. [PubMed: 25774885] [Full Text: https://doi.org/10.1210/jc.2015-1150]
Choi, Y., Jeon, S., Choi, M., Lee, M., Park, M., Lee D. R., Jun, K.-Y., Kwon, Y., Lee, O.-H., Song, S.-H., Kim, J.-Y., Lee, K.-A., Yoon, T. K., Rajkovic, A., Shim, S. H. Mutations in SOHLH1 gene associate with nonobstructive azoospermia. Hum. Mutat. 31: 788-793, 2010. [PubMed: 20506135] [Full Text: https://doi.org/10.1002/humu.21264]
Kumar, T. R. The SO(H)L(H) 'O' drivers of oocyte growth and survival but not meiosis I. J. Clin. Invest. 127: 2044-2047, 2017. [PubMed: 28504648] [Full Text: https://doi.org/10.1172/JCI94665]
Nakamura, S., Miyado, M., Saito, K., Katsumi, M., Nakamura, A., Kobori, Y., Tanaka, Y., Ishikawa, H., Yoshida, A., Okada, H., Hata, K., Nakabayashi, K., Okamura, K., Ogata, H., Matsubara, Y., Ogata, T., Nakai, H., Fukami, M. Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations. Andrology 5: 824-831, 2017. [PubMed: 28718531] [Full Text: https://doi.org/10.1111/andr.12378]
Pangas, S. A., Choi, Y., Ballow, D. J., Zhao, Y., Westphal, H., Matzuk, M. M., Rajkovic, A. Oogenesis require germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc. Nat. Acad. Sci. 103: 8090-8095, 2006. [PubMed: 16690745] [Full Text: https://doi.org/10.1073/pnas.0601083103]
Shin, Y.-H., Ren, Y., Suzuiki, H., Golnoski, K. J., won Ahn, H., Mico, V., Rajkovic, A. Transcription factors SOHLH1 and SOHLH2 coordinate oocyte differentiation without affecting meiosis I. J. Clin. Invest. 127: 2106-2117, 2017. [PubMed: 28504655] [Full Text: https://doi.org/10.1172/JCI90281]
Stumpf, A. L. Personal Communication. Baltimore, Md. 09/25/2017.
Suzuki, H., Ahn, H. W., Chu, T., Bowden, W., Gassei, K., Orwig, K., Rajkovic, A. SOHLH1 and SOHLH2 coordinate spermatogonial differentiation. Dev. Biol. 361: 301-312, 2012. [PubMed: 22056784] [Full Text: https://doi.org/10.1016/j.ydbio.2011.10.027]