A novel point mutation in cluster 3 of the thyroid hormone receptor β gene (P247L) causing mild resistance to thyroid hormone

Joachim Pohlenz, Laura Manders, Peter M. Sadow, Prakash C. Kansal, Samuel Refetoff, Roy E Weiss

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) β gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31- year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRβ gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRβ had a Ka for triiodothyronine (T3) 30% that of the wild-type TRβ, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to <0.01 μU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRβ but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRβ mutation is associated with a relatively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.

Original languageEnglish (US)
Pages (from-to)1195-1203
Number of pages9
JournalThyroid
Volume9
Issue number12
StatePublished - Dec 1999
Externally publishedYes

Fingerprint

Thyroid Hormone Resistance Syndrome
Thyroid Hormone Receptors
Point Mutation
Mutation
Thyroid Hormones
Genes
Serum
Thyroid Function Tests
Wechsler Scales
Basal Metabolism
Sex Hormone-Binding Globulin
Thyroid Diseases
Goiter
Triiodothyronine
Thyrotropin
Ferritins
Creatine Kinase
Intelligence
Thyroxine
Reporter Genes

ASJC Scopus subject areas

  • Endocrinology

Cite this

A novel point mutation in cluster 3 of the thyroid hormone receptor β gene (P247L) causing mild resistance to thyroid hormone. / Pohlenz, Joachim; Manders, Laura; Sadow, Peter M.; Kansal, Prakash C.; Refetoff, Samuel; Weiss, Roy E.

In: Thyroid, Vol. 9, No. 12, 12.1999, p. 1195-1203.

Research output: Contribution to journalArticle

Pohlenz, J, Manders, L, Sadow, PM, Kansal, PC, Refetoff, S & Weiss, RE 1999, 'A novel point mutation in cluster 3 of the thyroid hormone receptor β gene (P247L) causing mild resistance to thyroid hormone', Thyroid, vol. 9, no. 12, pp. 1195-1203.
Pohlenz, Joachim ; Manders, Laura ; Sadow, Peter M. ; Kansal, Prakash C. ; Refetoff, Samuel ; Weiss, Roy E. / A novel point mutation in cluster 3 of the thyroid hormone receptor β gene (P247L) causing mild resistance to thyroid hormone. In: Thyroid. 1999 ; Vol. 9, No. 12. pp. 1195-1203.
@article{80e2f706f971435a8c4b945aae0cfd63,
title = "A novel point mutation in cluster 3 of the thyroid hormone receptor β gene (P247L) causing mild resistance to thyroid hormone",
abstract = "Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) β gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31- year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRβ gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRβ had a Ka for triiodothyronine (T3) 30{\%} that of the wild-type TRβ, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to <0.01 μU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15{\%}-25{\%}, serum creatine kinase decreased by 15{\%} in two subjects and increased 35{\%} in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRβ but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRβ mutation is associated with a relatively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.",
author = "Joachim Pohlenz and Laura Manders and Sadow, {Peter M.} and Kansal, {Prakash C.} and Samuel Refetoff and Weiss, {Roy E}",
year = "1999",
month = "12",
language = "English (US)",
volume = "9",
pages = "1195--1203",
journal = "Thyroid",
issn = "1050-7256",
publisher = "Mary Ann Liebert Inc.",
number = "12",

}

TY - JOUR

T1 - A novel point mutation in cluster 3 of the thyroid hormone receptor β gene (P247L) causing mild resistance to thyroid hormone

AU - Pohlenz, Joachim

AU - Manders, Laura

AU - Sadow, Peter M.

AU - Kansal, Prakash C.

AU - Refetoff, Samuel

AU - Weiss, Roy E

PY - 1999/12

Y1 - 1999/12

N2 - Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) β gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31- year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRβ gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRβ had a Ka for triiodothyronine (T3) 30% that of the wild-type TRβ, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to <0.01 μU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRβ but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRβ mutation is associated with a relatively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.

AB - Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) β gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31- year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRβ gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRβ had a Ka for triiodothyronine (T3) 30% that of the wild-type TRβ, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to <0.01 μU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRβ but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRβ mutation is associated with a relatively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.

UR - http://www.scopus.com/inward/record.url?scp=0033399252&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033399252&partnerID=8YFLogxK

M3 - Article

C2 - 10646658

AN - SCOPUS:0033399252

VL - 9

SP - 1195

EP - 1203

JO - Thyroid

JF - Thyroid

SN - 1050-7256

IS - 12

ER -