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

Stephen J. Usala, Gregory E. Tennyson, Allen E. Bale, Robert W. Lash, Neil Gesundheit, Fredric E. Wondisford, Domenico Accili, Peter Hauser, Bruce D. Weintraub

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)93-100
Number of pages8
JournalJournal of Clinical Investigation
Volume85
Issue number1
StatePublished - Jan 1990
Externally publishedYes

Fingerprint

Thyroid Hormone Resistance Syndrome
Thyroid Hormone Receptors
erbA Genes
Mutation
Complementary DNA
Phenotype
Cytosine
Triiodothyronine
Adenine
Cytoplasmic and Nuclear Receptors
Thyroid Hormones
Histidine
Proline
Codon
Genetic Recombination
Leukocytes
Fibroblasts
Alleles
DNA

Keywords

  • Candidate mutation
  • Histidine
  • Linkage
  • Proline codon 448
  • Triiodothyronine-binding domain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Usala, S. J., Tennyson, G. E., Bale, A. E., Lash, R. W., Gesundheit, N., Wondisford, F. E., ... Weintraub, B. D. (1990). A base mutation of the C-erbAβ thyroid hormone receptor in a kindred with generalized thyroid hormone resistance: Molecular heterogeneity in two other kindreds. Journal of Clinical Investigation, 85(1), 93-100.

A base mutation of the C-erbAβ thyroid hormone receptor in a kindred with generalized thyroid hormone resistance : Molecular heterogeneity in two other kindreds. / Usala, Stephen J.; Tennyson, Gregory E.; Bale, Allen E.; Lash, Robert W.; Gesundheit, Neil; Wondisford, Fredric E.; Accili, Domenico; Hauser, Peter; Weintraub, Bruce D.

In: Journal of Clinical Investigation, Vol. 85, No. 1, 01.1990, p. 93-100.

Research output: Contribution to journalArticle

Usala, SJ, Tennyson, GE, Bale, AE, Lash, RW, Gesundheit, N, Wondisford, FE, Accili, D, Hauser, P & Weintraub, BD 1990, 'A base mutation of the C-erbAβ thyroid hormone receptor in a kindred with generalized thyroid hormone resistance: Molecular heterogeneity in two other kindreds', Journal of Clinical Investigation, vol. 85, no. 1, pp. 93-100.
Usala, Stephen J. ; Tennyson, Gregory E. ; Bale, Allen E. ; Lash, Robert W. ; Gesundheit, Neil ; Wondisford, Fredric E. ; Accili, Domenico ; Hauser, Peter ; Weintraub, Bruce D. / A base mutation of the C-erbAβ thyroid hormone receptor in a kindred with generalized thyroid hormone resistance : Molecular heterogeneity in two other kindreds. In: Journal of Clinical Investigation. 1990 ; Vol. 85, No. 1. pp. 93-100.
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abstract = "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.",
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AU - Gesundheit, Neil

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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.

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