Disorders of sex development: clinically relevant genes involved in gonadal differentiation

Discov Med. 2012 Nov;14(78):301-9.

Abstract

After the characterization of the sex-determining region of Y (SRY) in 1990, there have been an increasing number of genes recognized to play a role in sex development. The most common disorders of sex development (DSD) result from disruption of androgen levels and activity that affect later embryonal development, such as congenital adrenal hyperplasia and androgen insensitivity syndrome. However, genetic diagnosis of mutations affecting early gonadal development is becoming increasingly accessible to clinicians. More powerful genetic techniques are allowing for interrogation of the entire genome for causative changes and it is important to be able to critically assess the flood of genetic data for meaningful information. Recent discoveries have clarified the role of a variety of transcription factors in DSD such as SOX9, SF1, and WT1. Additionally, disruptions of signaling molecules such as hedgehog, WNT, cyclin-dependent kinase, and Ras/MAP kinase are now known to cause DSD. The dosage-dependence of genes involved in gonadal development is a recurrent theme, and genetic changes in promoter and repressor regions are being revealed by chromosomal microarray analysis and other techniques. In some cases, there are multiple different phenotypes caused by deletion, duplication, homozygous, heterozygous, and regulatory-region changes in the same gene. We aim to provide a concise and clinically-applicable overview of recent developments in the understanding of DSD caused by genetic changes affecting gonadal development.

Publication types

  • Review

MeSH terms

  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology
  • Humans
  • Male
  • RNA Splicing Factors
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Sexual Development / genetics
  • Sexual Development / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • WT1 Proteins / genetics
  • WT1 Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • RNA Splicing Factors
  • SF1 protein, human
  • SOX9 Transcription Factor
  • Transcription Factors
  • WT1 Proteins