MOLECULAR BASIS OF CONGENITAL THYROTROPIN DEFICIENCY

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DESCRIPTION (Adapted from applicant's description): Congenital hypothyroidism (CH) is one of the most common causes of preventable mental and growth retardation, with a collective incidence of 1:3-4,000 births. Early diagnosis and treatment is critical to the prevention of life-long debility because there is an inverse relationship between the age at which treatment is initiated and eventual psychometric outcomes. Thyroid hormone acts globally to activate metabolism and is required for normal growth and neonatal development of the brain and immune system. Thyroid hormone secretion is a finely regulated process that depends on a hormone cascade of the hypothalamus, pituitary gland, and thyroid gland. Though less common, CH due to pituitary defects present a particular diagnostic challenge to neonatal screening programs, resulting in delay of treatment. There has been no animal model of pituitary CH from which one might gain insight into such issues as the loss of thyrotropin-releasing hormone (TRH)-mediated functions in organs other than the pituitary gland. An inherited form of CH resulting in disproportionate growth delay, male hypofertility, and behavioral abnormalities was identified in a canine family. TRH-stimulation testing and hormone analysis demonstrated that the disorder is caused by failure of the pituitary gland to increase thyrotropin (TSH) secretion appropriately in affected dogs in spite of low thyroid hormone concentrations. The longterm goals of this investigation are to characterize and use this unique animal model of human CH to better understand normal pituitary function, non-thyroid gland-mediated functions of thyrotropin, and the pathogenesis of deficient TRH signaling. Immediately the investigators proposed to determine the molecular basis of the disorder in order to give added significance to future studies of pathogenesis. The specific aims of this proposal are: 1) to maintain a breeding colony of CH dogs and to perform matings which extend the CH family in a way that is most informative for candidate gene linkage studies, 2) to examine the TRH-mediated signal transduction pathway of TSH secretion by measuring TRHstimulated calcium ion currents in affected and normal dog cells in order to generate candidate gene hypotheses, and 3) to investigate the molecular basis of canine CH by examining candidate disease genes. Initial emphasis will be analysis of the candidate gene encoding the TRH receptor.