Kidney stones are a major clinical and economic health burden. Up to 50% of individuals who have formed a kidney stone will experience a second stone episode within 10 years of presentation and renal stone formers are at increased risk of chronic kidney disease. Unfortunately, current prevention strategies are relatively ineffective and the systemic and renal tubular mechanisms underlying this disease are poorly understood, thereby limiting opportunities to develop novel treatments. My research aim is to increase understanding of the pathophysiology of renal stone disease and to identify new therapeutic targets for the prevention of kidney stone recurrence.
Kidney stone formation may be due to rare monogenic disorders or, more commonly, be the result of a multifactorial process involving both genetic and environmental influences. I study both monogenic and polygenic factors that increase risk of nephrolithiasis. As a DPhil student and post-doctoral scientist, I focused on disorders of the calcium sensing receptor (CaSR) signalling pathway. Loss-of-function mutations of the CaSR cause familial hypocalciuric hypercalcaemia type 1 (FHH1), whilst gain-of-function mutations are associated with autosomal dominant hypocalcaemia (ADH), which is associated with hypercalciuria, and therefore an increased risk of renal stone formation, in ~10% of individuals. However, 35% of cases of FHH and 60% of cases of ADH are not due to CaSR mutations. I demonstrated that FHH type 2 (FHH2) and the new clinical disorder, ADH type 2 (ADH2), are due to loss- and gain-of-function mutations in the G-protein subunit, Gα11, respectively; a protein through which the CaSR signals. I have also demonstrated that FHH3 is due to loss-of-function mutations in the adaptor protein 2 sigma subunit, AP2σ2, due to impaired CaSR endocytosis. Furthermore, I have demonstrated that these signalling defects can be rectified using the CaSR allosteric modulator cinacalcet. These studies have facilitated improved molecular diagnosis of FHH and ADH and enabled better treatment of FHH3.