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Mechanisms of Disease: transcription factors in sex determination—relevance to human disorders of sex development

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 231–238 (2006)Cite this article

Abstract

Sex determination is the series of molecular events that direct the undifferentiated bipotential gonad to become either a testis or an ovary. In humans, disruption of this process results in intersexuality, also referred to as disorders of sex development (DSD). Despite the discovery of the sex-determining gene SRY (sex-determining region Y) 15 years ago, the molecular mechanisms of sex determination remain poorly understood. Analysis of clinically relevant mutations of sex-determining genes in individuals with DSD has provided considerable insight into the function of these genes. The majority of disorders of sex determination with known causes are explained by mutations in one of three transcription factors at the core of the sex-determining pathway: SRY, SOX9 (SRY-box 9) and NR5A1 (nuclear receptor subfamily 5, group A, member 1). These mutations either affect the level of protein available at its nuclear site of action (via changes in regulatory sequences, deletions, non-sense mutations or mutations in nuclear localization sequences), or alter the structure of the protein (via modifications of binding or bending activity, or of interactions with other proteins). Deciphering the functional diversity of the mutations affecting the sex-determining pathway has immediate clinical impact on the diagnosis, outcome studies and classification of patients with DSD.

Key Points

  • The known molecular mechanisms of sex determination involve a growing network of genes, a large number of which are transcription factors

  • The transcription factors so far identified as having a major role in sex determination, namely SRY, SOX9 and NR5A1, can be disrupted by a number of mutations that can affect either their availability in the nucleus or their function

  • The types of mutations found in SRY, SOX9 and NR5A1 can be used as a guideline when screening additional transcription factors postulated to be part of the sex-determining cascade

  • Advances in our molecular understanding of intersexuality should be paralleled by a corresponding effort to improve the nomenclature used in diagnosing patients with disorders of sex development

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Figure 1: Schematic representation of the transcription factors SRY (sex-determining region Y), SOX9 (SRY-box 9), and NR5A1 (nuclear receptor subfamily 5, group A, member 1)

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Authors and Affiliations

  1. graduate student in the Department of Human Genetics at UCLA School of Medicine, Los Angeles, CA, USA

    Ganka Nikolova

  2. Human Genetics, Pediatrics and Urology at UCLA School of Medicine,

    Eric Vilain

  3. Mattel's Children's hospital at UCLA, Los Angeles, CA, USA

    Eric Vilain

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  1. Ganka Nikolova
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  2. Eric Vilain
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Correspondence to Eric Vilain.

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Nikolova, G., Vilain, E. Mechanisms of Disease: transcription factors in sex determination—relevance to human disorders of sex development. Nat Rev Endocrinol 2, 231–238 (2006). https://doi.org/10.1038/ncpendmet0143

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