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A New Point Mutation in the 3,5,3'-Triiodothyronine-Binding Domain of the c-erbAβ Thyroid Hormone Receptor Is Tightly Linked to Generalized Thyroid Hormone Resistance

Department of Medicine, East Carolina University School of Medicine (S.J.U., J.B.M., T.L.W.) Greenville, North Carolina 27858–4354
Institut du Cancer de Montreal (J.B., W.E.C.B.) Montreal, Canada H2L 4M1
the Department of Human Genetics, Yale University (A.E.B.) New Haven, Connecticutt 06510–8005
the Molecular, Cellular, and Nutritional Endocrinology Branch, National Institutes of Health (R.W.L, B.D.W.) Bethesda, Maryland 20892

Address all correspondance and requests for reprints to: Stephen J. Usala, M.D., Ph.D., Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858–4354.

Two different mutations in the c-erbAβ thyroid hormone receptor have recently been reported as genetic abnormalities responsible for the syndrome of generalized thyroid hormone resistance (GTHR). We have now found in a third kindred, D, in which GTHR is inherited as a dominant disease, a new point mutation in the T₃-binding domain of c-erbAβ. A guanine to cytosine base substitution at nucleotide position 1305, which altered codon-335 from glutamine (CAG) to histidine (CAC), was found in one allele of 10 affected members and was not found in 6 unaffected members. This C-1305 sequence was not present in 106 random alleles, indicating that it was a mutation in c-erbAβ, and it was tightly linked to GTHR in kindred D, with a maximum logarithm of the odds score of 4.19 at a recombination fraction of 0. The tight linkage result confirms that GTHR maps to the c-erbAβ locus in multiple kindreds. In view of the tight linkage between the C-1305 mutation and GTHR, and that this mutation is a nonconservative alteration in a crucial region of the T₃-binding domain, it is probably the genetic defect in kindred D responsible for GTHR. The kindred D receptor appears to result in a different phenotype of tissue resistance compared to the previously reported kindred A receptor with a mutation in the carboxy-terminus of c-erbAβ.

^* Present address: Division of Endocrinology, University of Maryland School of Medicine, Baltimore, Maryland 21201.

Received June 6, 1990.

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