Stem Cell Medicine

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Gonadal Disorders

The Reproductive Development group is led by Professor Andrew Sinclair, and uses human genomics, developmental biology and stem cells approaches to understand gonad failure and dysfunction, improving diagnosis and ultimately patient outcomes.


Research Summary

Gonadal disorders is an umbrella term that refers to a wide spectrum of genetic disorders that impact the reproductive organs. There are many types of Gonadal Disorders and their effect on the external and internal reproductive organs can vary significantly. Occurring in around 1 in 4000 births, these disorders can result in ambiguous genitalia, infertility and are associated with paediatric cancers of the testes and ovaries. The cause is often a breakdown of the complex network of genes responsible for proper development of testes or ovaries in the embryo, a process known as ‘gonadal differentiation’.

Some of the more common types of Gonadal Disorders include gonadal dysgenesis, premature ovarian failure and androgen insensitivity syndrome (AIS), however there are many less common disorders, and in some cases it is not possible to make a clear diagnosis of the underlying condition.  Uncertainty about a child’s sex may be extremely traumatic for the individual, parents and other family members and carries profound psychological and reproductive consequences for the patient. Knowing the genetic cause can improve patient outcomes and wellbeing and aid in reproductive decisions, yet currently only 43% of patients with gonadal disorders can be provided with a molecular genetic diagnosis.  Advances in genomic technologies however, allow us to uncover a wide spectrum of candidate gene variants that may provide explanations for these conditions. 

Confirming exactly which of these gene variants are the cause of disease is difficult, as any useful analysis requires tissue samples from the patient’s gonads and this is often impossible to obtain.  The Reproductive Development group at MCRI Stem Cell Medicine however, use cutting edge human stem cell and gene editing technologies to solve this problem.  We can now take a few patient skin cells and make these into stem cells. These stem cells can then be differentiated into gonad cell types in order to mimic early gonad development.  This gives our researchers unprecedented insights into gonad development within the embryo and provides a highly sought-after in vitro (in a dish) model for analyzing the genetic causes of gonad disorders.


Modelling gonad disorders in a dish using patient derived stem cells

Formation of the gonads and their differentiation into testes or ovaries is central to human sex development.  In humans, any breakdown in this embryonic developmental process can cause disorders in gonad development, which may result in a range of symptoms including ambiguous genitalia. Within the MCRI Reproductive Development lab, we have developed a procedure that allows us to differentiate human stem cells into gonad cells types, with the overarching aim of creating a “testis or ovary in a dish”. This will allow us to model patient derived gene variants to understand their impact on gonad development.

Generation of gonad cell-specific reporter cell lines

Our researchers are using fluorescent tags on specific gonad cell lines in a dish, to allow easy identification of key testis cell types, such as Sertoli and Leydig cells. These cells perform the primary testicular functions; maintenance of germ cells and generation of sex steroids. Being able to identify these cell types means they can be isolated and characterised in great detail. A similar approach will be taken to optimise the differentiation of ovarian cell lineages. These human model systems will be an extremely valuable tool, providing insight into the earliest events and molecular pathways involved in human gonad development.


Robevska G, Ayers KL*, Sinclair AH. (2017) Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development. Disorders of Sex Development Human Mutation, 39(1):124-139.

Eggers S, Sadedin S, van den Bergen J ... Oshlack A, Ayres, K, and Sinclair AH. (2016) Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort. Genome Biology 17(1):243-264.

Tucker EJ, Grover SR, Bachelot A, Touraine P, and Sinclair AH (2016) Premature Ovarian Insufficiency: New perspectives on genetic cause and phenotypic spectrum. Endocrine Reviews 37(6): 609-635.

Ayers KL ... Sinclair AH, Oshlack A, and Smith CA (2013) RNA sequencing reveals sexually dimorphic gene expression before gonadal differentiation in chicken embryos and allows comprehensive annotation of W-chromosome genes. Genome Biology. 14(3):R26.

Sutton E ... Sinclair AH, Lovell-Badge R, and Thomas P (2011) Identification of Sox3/SOX3 as a XX male sex reversal gene in mice and humans. J Clinical Investigation, 121(1):328-41.

Smith CA, Roeszler K, Ohnesorg T, Farlie P, and Sinclair AH (2009) The conserved avian Z-linked gene, DMRT1, is required for male sex determination in the chicken. Nature 461(7261):267-271.

Smith CA, McClive P, Western PS, Reed K, and Sinclair AH (1999) Evolution - Conservation of a sex-determining gene. Nature, 402(6762):601-602.

Sinclair AH ... and Goodfellow PN. (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature, 346(6281):240-245.

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