A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds.

This is the authors' abstract. We don't add key points for this paper.

Generalized thyroid hormone resistance (GTHR) is a disorder of thyroid hormone action that we have previously shown to be tightly linked to one of the two thyroid hormone receptor genes, c-erbA,8, in a single kindred, A. We now show that in two other kindreds, B and D, with differing phenotypes, there is also linkage between c-erbAft and GTHR. The combined maximum logarithm of the odds score for all three kindreds at a recombination fraction of 0 was 5.77. In vivo studies had shown a triiodothyronine (T3)-binding affinity abnormality in nuclear receptors of kindred A, and we therefore investigated the defect in c-erbA,8 in this kindred by sequencing a major portion of the T3-binding domain in the 3'-region of fibroblast c-erbAfl cDNA and leukocyte c-erbAf genomic DNA. A base substitution, cytosine to adenine, was found at cDNA position 1643 which altered the proline codon at position 448 to a histi- dine. By allelic-specific hybridization, this base substitution was found in only one allele of seven affected members, and not found in 10 unaffected members of kindred A, as expected for a dominant disease. Also, this altered base was not found in kindreds B or D, or in 92 random c-erbA,8 alleles. These re- sults and the fact that the mutation is predicted to alter the secondary structure of the crucial T3-binding domain of the c-erbAft receptor suggest this mutation is an excellent candi- date for the genetic cause of GTHR in kindred A. Different mutations in the c-erbAfl gene are likely responsible for the variant phenotypes of thyroid hormone resistance in kindreds B and D. (J. Clin. Invest. 1990.85:93-100.) linkage -candidate mutationproline codon 448 * histidinetriiodothyronine-binding domain Introduction Generalized thyroid hormone resistance (GTHR)' refers to a syndrome characterized by elevated circulating levels of free thyroid hormones, resistance to thyroid hormone action, and inappropriately normal or elevated levels of thyroid-stimulat-