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. In this work published by CGM associate member Ravi Balasubramanian, CGM senior associate member Stephanie Seminara, and CGM investigator Bill Crowley, exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) was mined for pathogenic SOX2 variants. They identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes, going on to determine that Sox2 is highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression, and suppression of mouse SOX2 protein increased the levels of human kisspeptin, which has previously been invoked in IHH. These data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.