Elucidating the genetic and environmental determinants of congenital hypothyroidism

I first identified mutations in the anion transporter SLC26A7 as a novel genetic cause of human and murine congenital hypothyroidism (CH), but its molecular role in thyroid hormonogenesis remains unclear. I will investigate SLC26A7 function in cultured primary thyrocytes, initially evaluating its role in pH regulation, seeking new insights into thyroid hormone biosynthesis. The incidence of CH with a normally-located gland-in-situ (GIS CH) is increasing, but its determinants are poorly defined. In a case-control study, I will investigate the roles of genetic variants, micronutrients (iodine, selenium, iron) and endocrine disruptors (perchlorate, thiocyanate and nitrate), in the pathogenesis of permanent and transient GIS CH. Confirmed involvement of environmental factors will have public health ramefications and mandate future trials of micronutrient supplementation for treatment or prevention of CH. The study will also provide insights into the aetiology of transient CH, a clinically important entity for which the cause is largely unknown. DUOX2/DUOXA2 mutations impair thyroidal H2O2 production, often causing transient CH. I will investigate whether maternal heterozygosity for DUOX2/DUOXA2 mutations in association with increased gestational demand for thyroid hormone biosynthesis, causes hypothyroidism during pregnancy. Gestational thyroid dysfunction would mandate future studies of childhood neurodevelopmental outcome and levothyroxine treatment in such patients.