We investigate the genetic, molecular and physiological basis of endocrine disorders that affect calcium homeostasis, and endocrine tumour development. By identifying and understanding the underlying mechanisms, we aim to establish better diagnostic methods and develop novel targeted therapies for these disorders to improve patient care.
Our research activities encompass finding novel genetic causes and developing novel therapies for the following three areas:
Endocrine tumours – studies of genetics and cellular biology leading to new therapies.
Endocrine tumours, particularly in the parathyroid, pituitary and pancreas, may develop spontaneously, or in families, and individually or in association with each other eg in multiple endocrine neoplasia type 1 (MEN1).
MEN1 is an inherited syndrome, caused by loss-of-function mutations of the MEN1 gene (encoding the tumour suppressor protein menin). Patients may develop parathyroid, pituitary and/or pancreatic tumours that over-secrete hormones. MEN1 mutations are also found in sporadic tumours. We aim to better understand the function of menin, and its putative role in epigenetic regulation.
Endocrine tumours are usually removed by surgery. However, this is not always possible, and medical therapies are sub-optimal. Improved treatments are therefore needed. We are investigating MEN1 gene-replacement therapy (a pilot study of which restored menin expression and reduced proliferation of pituitary tumours in vivo), and studies of epigenetic modifying drugs (which reduced endocrine tumour cell proliferation).
Calcium-sensing by a G-protein coupled receptor - signalling and trafficking
The calcium sensing receptor (CaSR) is a G-protein coupled receptor that plays a critical role in calcium homeostasis, the importance of which is highlighted by human mutations within the CASR gene, which cause familial hypocalciuric hypercalcaemia (FHH) (inactivating mutations), and autosomal dominant hypocalcaemia (ADH) (activating mutations). Similarly, germline mutations in Gα11, the G-protein with which CaSR predominantly signals, also cause FHH and ADH.
By studying disease-causing mutations, we have shown that CaSR mutations within the same ‘switch’ residues, which act as gatekeepers for calcium binding, can cause FHH and ADH, and that Gαq/11 mutations cluster within key structural domains to disrupt CaSR signalling. By studying CaSR and Gα11 mutations in vitro and in vivo we aim to better understand CaSR structure-function and signalling, to inform design of novel therapies for CaSR-related disorders.
Mutations in the adaptor protein 2 (AP2) σ-subunit cause a third type of FHH. The tetrameric AP2 plays a critical role in clathrin-mediated endocytosis, a process that is vital for transmembrane protein internalisation. We are investigating the effect of AP2σ mutations on CaSR trafficking, and how this affects receptor signalling pathways.
Rare monogenic kidney and skeletal disorders
Dent’s disease, which is associated with rickets, kidney stones and renal failure, and is due to mutations in CLC-5, a chloride-proton antiporter. CLC-5 mutations disrupt endocytosis within kidney tubules resulting in reduced protein reabsorption and we are using cellular models to investigate these processes mechanistically.
Familial juvenile hyperuricaemic nephropathy (FJHN), which is associated with renal fibrosis and is due to mutations in uromodulin. We are studying how uromodulin mutations cause protein misfolding and how this leads to renal fibrosis.
Marshall-Smith Syndrome (MSS), which is characterised by abnormal bone formation, and mental and motor retardation, and is caused by mutations in the NFIX gene. We aim to determine the effect of MSS-associated mutations on NFIX functions.
Patient Support Groups
We have a strong track record in engaging with the public, to facilitate understanding of our scientific advances. Prof Thakker is patron of the patient support group Association for Multiple Endocrine Neoplasia Disorders (AMEND), a member of their Medical Advisory Team, and has helped to provide advice, and written patient information booklets. He is also a member of the Medical Advisory Team for Hypopara UK. Prof Thakker and members of the research group present at patient group (AMEND, Hypopara UK, Lowe-Syndrome, Marshall-Smith Syndrome) annual meetings, and also ensure that patients are represented at workshops/meetings, by securing invitations from programme organising committees.
Schools and Outreach Events
Prof Thakker is a Governor of Oxford High School (Girl’s Day School Trust, GDST) and has given talks about genetic advances in medicine as well as organising work-experience programmes for pupils. In addition, Prof Thakker and members of the group participate in outreach events, such as open days for public engagement at University of Oxford, Oxford University Hospitals Trust and the Oxfordshire Science Festival.