The role of DHEA sulfation in the pre-receptor regulation of androgen excess. (360G-Wellcome-092283_Z_10_Z)
DHEA is the major precursor of androgen synthesis via the classic pathway unless inactivated to DHEAS by DHEA sulfotransferase, which requires the universal sulfate donor PAPS for catalytic activity. We have identified inactivating mutations in PAPSS2 encoding PAPS synthase 2 in a girl presenting with premature pubarche followed by development of PCOS. These findings have established PAPSS2 deficiency as a novel monogenic cause of androgen excess, revealing DHEA sulfation as a gatekeeper to huma n androgen synthesis. In this project we will aim to identify and characterise further PAPSS2 mutations in patients with premature pubarche and PCOS, also exploring the possibility of novel mutations in other elements of the DHEA sulfation system. Taking a cell-based in vitro approach we will seek to identify novel pre-receptor mechanisms involved in the regulation of DHEA sulfation, including enzymes and transporters. Finally, we will examine whether common genetic variation in PAPSS2 contribut es to PCOS susceptibility by performing dense tagSNP genotyping in large PCOS and control cohorts. Taken together, this research project will investigate the physiological and clinical significance of a crucial metabolic pathway, with its impact extending beyond steroidogenesis and androgen excess to impaired sulfation in liver, bone and steroid-dependent tumours.
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Grant Details
Amount Awarded | 309491 |
Applicant Surname | Arlt |
Approval Committee | Physiological Sciences Funding Committee |
Award Date | 2010-07-06T00:00:00+00:00 |
Financial Year | 2009/10 |
Grant Programme: Title | Project Grant |
Internal ID | 092283/Z/10/Z |
Lead Applicant | Prof Wiebke Arlt |
Partnership Value | 309491 |
Planned Dates: End Date | 2014-09-30T00:00:00+00:00 |
Planned Dates: Start Date | 2011-10-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | West Midlands |