Endocrine Abstracts

In my lecture, I will present notable contributions of our group in the field of thyroid hormone action. We have defined a multisystem disorder, often presenting in childhood, caused by mutations in SECISBP2, a factor which controls the synthesis of proteins (including deiodinase enzymes) which contain the aminoacid selenocysteine. This syndrome is associated with disordered thyroid hormone metabolism and phenotypes (e.g. muscular dystrophy, azoospermia) due to deficiency of selenoproteins in specific tissues plus features (e.g. photosensitivity, progressive hearing loss, aortic aneurysm) secondary to the lack of selenoenzymes which breakdown reactive oxygen species in cells. This disorder is a unique exemplar of the adverse consequences of oxidative stress in humans. We have discovered diverse mutations in THRB, causing Resistance to Thyroid Hormone (RTH) beta. We were first to discover homologous mutations in THRA causing RTHalpha - a form of congenital hypothyroidism which is underdiagnosed because thyroid function tests are near-normal; we first described and dominant negative mutations in PPARG, causing lipodystrophic insulin resistance. In these disorders, I will show that heterozygous mutant receptors inhibit the function of their normal cellular counterparts in a dominant negative manner - a unifying pathogenetic mechanism in these conditions and some other nuclear receptormediated disorders. Insights gained from the properties of unique receptor mutations and corresponding clinical phenotypes of prismatic cases, have enabled us to elucidate the molecular basis of dominant negative inhibition, informing approaches to treatment of these disorders.