Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms

• DOI: 10.1172/jci.insight.164324
• Publication Date: 2023-01-05T17:01:52Z
• Authors: Jessica Cassin; Maria I. Stamou; Kimberly W. Keefe; Kaitlin E. Sung; Celine C. Bojo; Karen J. Tonsfeldt; Rebecca A. Rojas; Vanessa Ferreira ...; Lacey Plummer; Kathryn B. Salnikov; David L. Keefe; Metin Ozata; Myron Genel; Neoklis A. Georgo...; Janet E. Hall; William F. Crowley; Stephanie B. Semi...; Pamela L. Mellon; Ravikumar Balasub...
• Keywords: Adult; 570; Heterozygote; Biomedical and clinical sciences; 610; Mice; 03 medical and health sciences; Rare Diseases; Endocrinology; Clinical Research; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Neuroendocrine regulation; 0303 health sciences; Biomedical and Clinical Sciences; Hypogonadism; SOXB1 Transcription Factors; Human Genome; Neurosciences; R; Health sciences; 3. Good health; Health Disparities; Phenotype; Mutation; Medicine; Female; Neuroscience; Research Article

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 large, well-phenotyped cohort of patients with idiopathic hypogonadism (IHH) for pathogenic to investigate the underlying and its associated phenotypes. identified 8 IHH individuals harboring heterozygous variable These variant proteins were tested in vitro determine whether causal relationship between exists. found Sox2 was highly expressed hypothalamus adult mice colocalized kisspeptin 1 (KISS1) expression anteroventral periventricular nucleus female mice. In vitro, shRNA suppression mouse protein Kiss-expressing cell lines increased levels human luciferase (hKiss-luc) transcription, while overexpression repressed hKiss-luc transcription. Further, 4 prevented this SOX2-mediated repression hKiss-luc. Together, these suggest contribute both anosmic normosmic forms IHH, attesting hypothalamic spectrum. Our study describes potentially novel mechanisms contributing SOX2-related disease highlights necessity screening genetic evaluation irrespective defects.