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Tight Linkage between the Syndrome of Generalized Thyroid Hormone Resistance and the Human c-erbAβ Gene

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda, Maryland 20892
National Cancer Institute, National Institutes of Health Bethesda, Maryland 20892
National Institute of Mental Health, National Institutes of Health Bethesda, Maryland 20892

Address requests for reprints to: Stephen J. Usala, National Institutes of Health, Building 10, Room 8D14, Bethesda, Maryland 20892.

Abstract

Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T₃ with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies have suggested quantitative or qualitative defects in T₃ binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA and c-erbAβ, we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbAβ locus on chromosome 3. This linkage strongly suggests that the c-erbAβ gene is important in man as a thyroid hormone receptor and identifies a putative c-erbAβ mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.

Received for publication August 9, 1988. Accepted for publication August 17, 1988.

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