Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms
Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadis...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-02-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.164324 |
| _version_ | 1797634367792611328 |
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| author | Jessica Cassin Maria I. Stamou Kimberly W. Keefe Kaitlin E. Sung Celine C. Bojo Karen J. Tonsfeldt Rebecca A. Rojas Vanessa Ferreira Lopes Lacey Plummer Kathryn B. Salnikov David L. Keefe Jr. Metin Ozata Myron Genel Neoklis A. Georgopoulos Janet E. Hall William F. Crowley Jr. Stephanie B. Seminara Pamela L. Mellon Ravikumar Balasubramanian |
| author_facet | Jessica Cassin Maria I. Stamou Kimberly W. Keefe Kaitlin E. Sung Celine C. Bojo Karen J. Tonsfeldt Rebecca A. Rojas Vanessa Ferreira Lopes Lacey Plummer Kathryn B. Salnikov David L. Keefe Jr. Metin Ozata Myron Genel Neoklis A. Georgopoulos Janet E. Hall William F. Crowley Jr. Stephanie B. Seminara Pamela L. Mellon Ravikumar Balasubramanian |
| author_sort | Jessica Cassin |
| collection | DOAJ |
| description | Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects. |
| first_indexed | 2024-03-11T12:06:41Z |
| format | Article |
| id | doaj.art-767994d5a65b43fab45a677b83b0584b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:41Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-767994d5a65b43fab45a677b83b0584b2023-11-07T16:25:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-02-0183Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanismsJessica CassinMaria I. StamouKimberly W. KeefeKaitlin E. SungCeline C. BojoKaren J. TonsfeldtRebecca A. RojasVanessa Ferreira LopesLacey PlummerKathryn B. SalnikovDavid L. Keefe Jr.Metin OzataMyron GenelNeoklis A. GeorgopoulosJanet E. HallWilliam F. Crowley Jr.Stephanie B. SeminaraPamela L. MellonRavikumar BalasubramanianPathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.https://doi.org/10.1172/jci.insight.164324EndocrinologyNeuroscience |
| spellingShingle | Jessica Cassin Maria I. Stamou Kimberly W. Keefe Kaitlin E. Sung Celine C. Bojo Karen J. Tonsfeldt Rebecca A. Rojas Vanessa Ferreira Lopes Lacey Plummer Kathryn B. Salnikov David L. Keefe Jr. Metin Ozata Myron Genel Neoklis A. Georgopoulos Janet E. Hall William F. Crowley Jr. Stephanie B. Seminara Pamela L. Mellon Ravikumar Balasubramanian Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms JCI Insight Endocrinology Neuroscience |
| title | Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms |
| title_full | Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms |
| title_fullStr | Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms |
| title_full_unstemmed | Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms |
| title_short | Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms |
| title_sort | heterozygous mutations in sox2 may cause idiopathic hypogonadotropic hypogonadism via dominant negative mechanisms |
| topic | Endocrinology Neuroscience |
| url | https://doi.org/10.1172/jci.insight.164324 |
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