The broad, long term objectives of this research proposal are to gain further knowledge on the mechanisms of thyroid hormone action and to improve our ability to diagnose and treat a group of conditions known as syndromes of generalized resistance to thyroid hormone (GRTH). In order to achieve these goals, I plan to study GRTH at the molecular level since most of, if not all, such patients are likely to have inherited defective thyroid hormone receptors. I have the largest collection of DNA, fibroblasts and available patients with GRTH making my ability to execute this project unique. Recently developed methods for the clinical diagnosis of these syndromes as well as the recent identification of the genes expressing thyroid hormone receptor proteins, allow the achievement of these objectives through the detailed study of these errors of nature.
Aim 1 will determine the prevalence of GRTH in ADHD. Patients suspected with the diagnosis of GRTH are: (a) referred to our clinic or (b) hopefully identified through a neonatal screening program with the state of Illinois; or (c) by screening children with the attention deficit/hyperactive disorder (ADHD), a condition suspected of having a high incidence of GRTH. These patients are then admitted to the Clinical Research Center (CRC) to confirm the diagnosis.
Aim 2 will assess the use of T3 in treatment of children with ADHD and GRTH. DNA from patients with clinically confirmed GRTH will be screened for abnormalities in the genes coding for the human thyroid hormone receptors (hTR). The physiological significance of the identified mutant hTR will be determined. Transcription and translation of the mutant gene will be done to allow assessment of the functional domains of the encoded molecules, namely, their thyroid hormone and DNA binding properties. As there are at least three different forms of TRs expressed in man (alphal, alpha2, and betal), the mechanism of action and interaction of these different receptors are unknown. By defining the mutations in patients with GRTH, this would contribute to the identification of physiologically relevant thyroid hormone receptor products and the position of amino acids important for the proper function of the DNA and hormone-binding domains.
|Hayashi, Y; Xie, J; Weiss, R E et al. (1998) Selective pituitary resistance to thyroid hormone produced by expression of a mutant thyroid hormone receptor beta gene in the pituitary gland of transgenic mice. Biochem Biophys Res Commun 245:204-10|
|Carvalho, G A; Weiss, R E; Refetoff, S (1998) Complete thyroxine-binding globulin (TBG) deficiency produced by a mutation in acceptor splice site causing frameshift and early termination of translation (TBG-Kankakee). J Clin Endocrinol Metab 83:3604-8|
|Weiss, R E; Tunca, H; Knapple, W L et al. (1997) Phenotype differences of resistance to thyroid hormone in two unrelated families with an identical mutation in the thyroid hormone receptor beta gene (R320C). Thyroid 7:35-8|
|Weiss, R E; Forrest, D; Pohlenz, J et al. (1997) Thyrotropin regulation by thyroid hormone in thyroid hormone receptor beta-deficient mice. Endocrinology 138:3624-9|
|Xie, J; Pannain, S; Pohlenz, J et al. (1997) Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH. J Clin Endocrinol Metab 82:3933-40|
|Weiss, R E; Stein, M A; Refetoff, S (1997) Behavioral effects of liothyronine (L-T3) in children with attention deficit hyperactivity disorder in the presence and absence of resistance to thyroid hormone. Thyroid 7:389-93|
|Weiss, R E; Refetoff, S (1996) Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin North Am 25:719-30|
|Weiss, R E; Tunca, H; Gerstein, H C et al. (1996) A new mutation in the thyroid hormone receptor (TR) beta gene (V458A) in a family with resistance to thyroid hormone (RTH). Thyroid 6:311-2|
|Refetoff, S; Marinov, V S; Tunca, H et al. (1996) A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. J Clin Endocrinol Metab 81:3335-40|
|Weiss, R E; Sunthornthepvarakul, T; Angkeow, P et al. (1995) Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred. J Clin Endocrinol Metab 80:116-21|
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