TY - JOUR
T1 - A new point mutation (C446R) in the thyroid hormone receptor-β gene of a family with resistance to thyroid hormone
AU - Weiss, Roy E.
AU - Chyna, Brent
AU - Duell, P. Barton
AU - Hayashi, Yoshitaka
AU - Sunthornthepvarakul, Thongkum
AU - Refetoff, Samuel
PY - 1994/5
Y1 - 1994/5
N2 - Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-β (TRβ) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3- binding domain of the TRβ gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (±SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 ± 21 vs. 108 ± 13; total T3, 4.3 ± 0.4 vs. 2.4 ± 0.4 nmol/L; and TSH, 4.5 ± 1.1 vs. 2.4 ± 1.1 mU/L. DNA samples from 18 family members were screened for the TRβ mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TRβ expressed in Cos-I cells did not bind T3 (K(a) of C446R/wild-type, <0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild- type TRβ.
AB - Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-β (TRβ) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3- binding domain of the TRβ gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (±SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 ± 21 vs. 108 ± 13; total T3, 4.3 ± 0.4 vs. 2.4 ± 0.4 nmol/L; and TSH, 4.5 ± 1.1 vs. 2.4 ± 1.1 mU/L. DNA samples from 18 family members were screened for the TRβ mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TRβ expressed in Cos-I cells did not bind T3 (K(a) of C446R/wild-type, <0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild- type TRβ.
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U2 - 10.1210/jc.78.5.1253
DO - 10.1210/jc.78.5.1253
M3 - Comment/debate
C2 - 8175986
AN - SCOPUS:0028324625
SN - 0021-972X
VL - 78
SP - 1253
EP - 1256
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -