A Base Mutation of the C - erbAfl Thyroid Hormone Receptor in a Kindred with Generalized Thyroid Hormone Resistance

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 histidine. 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 results 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 candidate 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 mutation proline codon 448 * histidine triiodothyronine-binding domain