Review
Human sex-determination and disorders of sex-development (DSD)

https://doi.org/10.1016/j.semcdb.2015.10.030Get rights and content

Abstract

Several new genes and pathways have been identified in recent years associated with human errors of sex-determination or DSD. SOX family gene mutations, as well as mutations involving GATA4, FOG2 and genes involved in MAP kinase signaling have been associated with virilization in 46,XX individuals or with 46,XY gonadal dysgenesis. Furthermore, mutations involving another key gene in sex-determination, NR5A1, are now known to be an important cause spermatogenic failure in the male and ovarian insufficiency in the female. These new findings offer insights into human sex-determination and highlight important differences between the human and mouse model.

This review will critically examine the evidence linking gene mutations, especially MAP3K1, to non-syndromic forms of human 46,XY gonadal dysgenesis or XX testicular/ovotesticular.

Introduction

DSD, defined as ‘congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical’ encompasses a wide spectrum of phenotypes [1]. This definition includes errors of primary sex-determination; 46,XY complete or partial gonadal dysgenesis (CGD, PGD; complete or partial absence of testis-determination) or 46,XX testicular DSD which refers to a male with testis and a normal male habitus and 46,XX ovotesticular DSD refers to individuals that have both ovarian and testicular tissue in the gonads. Our understanding of the genes involved in sex-determination and the mechanisms involved has improved dramatically over the past 10 years, however in cases of DSD a molecular diagnosis is still only made in only around 20% of DSD (excluding those cases where the biochemical profile indicates a specific steroidogenic block) [1]. Current data indicate that causal gene mutations can be found in around 50% of the patients who have errors of primary sex-determination. This review will focus on the gene mutations that result in human pathologies of primary sex-determination.

Section snippets

SRY and SOX9

Approximately 15% of all cases of 46,XY CGD carry mutations in the Y-linked testis-determining gene SRY with the majority of these mutations localized within the HMG-domain [2]. A few rare cases of gonadal dysgenesis with small interstitial deletions 5′ and 3′ to the SRY open-reading frame have also been described [3], [4]. In most cases the SRY mutations are de novo but some are inherited from an apparently normal and fertile father. Functional studies suggest that these inherited SRY

SOX genes and 46,XX testicular and ovotesticular DSD

SRY and the X-linked gene SOX3 are thought to share a common ancestor and during early mammalian evolution SRY arose from a gain-of-function mutation in the proto-Y allele of SOX3 that resulted in testis specific expression. Although Sox3 is normally not expressed in the urogenital ridge at the moment of sex-determination, it can substitute for Sry in testis determination. This is demonstrated by the ectopic expression of Sox3 in XX hemizygous transgenic gonads that induces Sox9 upregulation

RSPO1, WNT4, FOXL2 and 46,XX SRY-negative testicular and ovotesticular DSD

Mutations involving R-spondin1 (RSPO1) and WNT4 are associated with exceptionally rare syndromic forms of 46,XX testicular/ovotesticular DSD. RSPO1 belongs to a family of secreted furin-like domain containing proteins, which have pleiotropic functions in development and stem cell growth through their role in Wnt/β-catenin signaling. Rspo1−/− XX mice show partial female-to-male sex reversal possibly by antagonizing dickkopf-1 (Dkk1)-dependent internalization of LRP6, thereby resulting in a

Conclusions

The last 5 years have seen considerable advances in our knowledge of the genetic causes of 46,XY and 46,XX DSD due to rapid developments in -omic technologies and a greater awareness of DSD as a public health issue. The latter is leading to improved details descriptions of the DSD phenotypes/families and more knowledge-based diagnosis. Technologies for genomic analyses, such as high resolution comparative genome hybridization or genome sequencing are both improving in accuracy and become more

Acknowledgements

Supported by grants from the Agence Nationale de la Recherche-GIS Institut des Maladies Rares (to Dr. McElreavey); by a research grant from the EuroDSD in the European Community's Seventh Framework Program FP7/2007–2013 under grant agreement no. 201444 (McElreavey and Bashamboo).

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