TY - JOUR
T1 - A base mutation of the C-erbAβ thyroid hormone receptor in a kindred with generalized thyroid hormone resistance
T2 - Molecular heterogeneity in two other kindreds
AU - Usala, Stephen J.
AU - Tennyson, Gregory E.
AU - Bale, Allen E.
AU - Lash, Robert W.
AU - Gesundheit, Neil
AU - Wondisford, Fredric E.
AU - Accili, Domenico
AU - Hauser, Peter
AU - Weintraub, Bruce D.
PY - 1990/1
Y1 - 1990/1
N2 - 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-erbAβ, 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-erbAβ 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-erbAβ in this kindred by sequencing a major portion of the T3-binding domain in the 3′-region of fibroblast c-erbAβ cDNA and leukocyte c-erbAβ 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-erbAβ allelles. These results and the fact that the mutation is predicted to alter the secondary structure of the crucial T3-binding domain of the c-erbAβ receptor suggest this mutation is an excellent candidate for the genetic cause of GTHR in kindred A. Different mutations in the c-erbAβ gene are likely responsible for the variant phenotypes of thyroid hormone resistance in kindreds B and D.
AB - 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-erbAβ, 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-erbAβ 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-erbAβ in this kindred by sequencing a major portion of the T3-binding domain in the 3′-region of fibroblast c-erbAβ cDNA and leukocyte c-erbAβ 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-erbAβ allelles. These results and the fact that the mutation is predicted to alter the secondary structure of the crucial T3-binding domain of the c-erbAβ receptor suggest this mutation is an excellent candidate for the genetic cause of GTHR in kindred A. Different mutations in the c-erbAβ gene are likely responsible for the variant phenotypes of thyroid hormone resistance in kindreds B and D.
KW - Candidate mutation
KW - Histidine
KW - Linkage
KW - Proline codon 448
KW - Triiodothyronine-binding domain
UR - http://www.scopus.com/inward/record.url?scp=0025141255&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025141255&partnerID=8YFLogxK
M3 - Article
C2 - 2153155
AN - SCOPUS:0025141255
SN - 0021-9738
VL - 85
SP - 93
EP - 100
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -