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Citations to this article

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms
Jessica Cassin, … , Pamela L. Mellon, Ravikumar Balasubramanian
Jessica Cassin, … , Pamela L. Mellon, Ravikumar Balasubramanian
Published January 5, 2023
Citation Information: JCI Insight. 2023;8(3):e164324. https://doi.org/10.1172/jci.insight.164324.
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Research Article Endocrinology Neuroscience Article has an altmetric score of 3

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

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Abstract

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.

Authors

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

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Total citations by year

Year: 2025 2024 Total
Citations: 2 2 4
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2024 (2)

Title and authors Publication Year
A novel SOX2 frameshift pathogenic variant located in the transactivation domain in a male infant with hypogonadotropic hypogonadism
Kimura-Yoshida A, Sato T, Ichihashi Y, Wasa M, Narumi S, Ishii T, Hasegawa T
Clinical Pediatric Endocrinology 2024
Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders
Sun B, Stamou MI, Stockman SL, Campbell MB, Plummer L, Salnikov KB, Kotan LD, Topaloglu AK, Hisama FM, Davis EE, Seminara SB, Balasubramanian R
The Journal of Clinical Endocrinology and Metabolism 2024

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