Exploiting molecular genetic diagnoses of polycystic ovary syndrome to achieve better patient outcome

Silvia Sini-Laulu Borgen

Polycystic ovary syndrome (PCOS) is an endocrinopathy that affects 5% to 10% of women. It is the most common reproductive disorder in women and is characterised by menstrual irregularity, hyperandrogenism, and polycystic ovarian morphology. This disorder also involves a major risk factor for non-insulin dependent diabetes, hypertension, and cardiovascular disease. While PCOS is believed to have a complex genetic component, the exact nature of this component remains largely unknown. However, Genome Wide Association Studies (GWAS) and exome sequencing have begun to generate statistically significant and replicable data from which more specific investigations can be launched. PCOS related variants highlighted by these methods can then be the subject of functional studies that seek to identify the functional role that these variants may be involved in. The efficient uncovering of variants, including exomic identification and functional characterisation of the genetic lesions, can aid genetic diagnosis of PCOS, which in turn will help achieve better patient outcomes and provide the basis for targeted therapies. The focus of this study was that efficient genetic diagnosis of PCOS will be assisted by an increased understanding of the aetiology of PCOS gained via exome sequencing identification of related individuals and functional characterisation of variants. To this end, related individuals with clinically defined PCOS were recruited and exome sequencing carried out to uncover putative causal mutations. In addition, a functional study of growth differentiation factor-9 (GDF9) was conducted due to its role in folliculogenesis and female fertility, as well as its proximity to a PCOS linked variant (rs13164856) identified via a GWAS. A single 1-bp deletion mutation (783celC) in GDF9 was targeted, as this deletion is known to cause primary ovarian insufficiency. The possible functional role of this GDF9 variant was then tested using an in vitro model. This was achieved by creating mammalian expression vectors containing the wildtype and mutant sequences. The primary achievement of this thesis was the uncovering of causal putative mutations shared between first-degree relatives suffering from PCOS. This data will potentially aid in uncovering the aetiology of PCOS. Functional characterisation of the GDF9 mutation was unsuccessful due to failure of overexpression of the GDF9 mutant construct.

Exploiting molecular genetic diagnoses of polycystic ovary syndrome to achieve better patient outcome

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