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Macchia E, Agostini M, Sarkissian G, et al. Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor beta gene in an Italian kindred with resistance to thyroid hormone. J Endocrinol Invest. 1998;21(4):226-33doi: 10.1007/BF03347307.
Macchia, E., Agostini, M., Sarkissian, G., Giorgilli, G., Canale, D., Scartabelli, G., Margotat, A., Torresani, J., & Pinchera, A. (1998). Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor beta gene in an Italian kindred with resistance to thyroid hormone. Journal of endocrinological investigation, 21(4), 226-33. https://doi.org/10.1007/BF03347307
Macchia, E, et al. "Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor beta gene in an Italian kindred with resistance to thyroid hormone." Journal of endocrinological investigation vol. 21,4 (1998): 226-33. doi: https://doi.org/10.1007/BF03347307
Macchia E, Agostini M, Sarkissian G, Giorgilli G, Canale D, Scartabelli G, Margotat A, Torresani J, Pinchera A. Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor beta gene in an Italian kindred with resistance to thyroid hormone. J Endocrinol Invest. 1998 Apr;21(4):226-33. doi: 10.1007/BF03347307. PMID: 9624596.
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J Endocrinol Invest. 1998 Apr;21(4):226-33. doi: 10.1007/BF03347307.

Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor beta gene in an Italian kindred with resistance to thyroid hormone.

Journal of endocrinological investigation

E Macchia, M Agostini, G Sarkissian, G Giorgilli, D Canale, G Scartabelli, A Margotat, J Torresani, A Pinchera

Affiliations

  1. Istituto di Endocrinologia, Università di Pisa, Italy.

PMID: 9624596 DOI: 10.1007/BF03347307

Abstract

Resistance to thyroid hormone (RTH) is almost invariably associated with mutations of the thyroid hormone (TH) receptor beta (hTR beta) gene and is inherited as an autosomal dominant disease. Mutations of hTR beta identified in patients affected by RTH cluster generally at two spots of the ligand binding domain. We investigated whether an Italian kindred with RTH had a mutation in the thyroid hormone (TH) receptor beta gene. Blood samples were obtained from the available family members for biochemical and genetic analyses. Thyroid function tests in basal conditions, and in the case of the propositus also following incremental doses of T3, were performed. Exon 4 to 10 of hTR beta gene were amplified using the polymerase chain reaction (PCR) and the mutation was identified by direct sequence analysis. The affinity constant of this mutated receptor for T3 was measured by in vitro transcription-translation and was then compared with that of wild type. We identified a heterozygous G to A transition at nucleotide 1037 of exon 8 at codon 251, resulting in a glycine (G) to glutamic acid (E) substitution (G251E) in the patient affected by RTH and in his affected offspring, but not in the normal family members. This novel mutation represents a de novo mutation since both parents of the index case were unaffected and did not have this genomic mutation. When expressed in vitro, the mutant protein (G251E) showed a marked decrease of the affinity for T3, suggesting an impaired ligand-dependent transactivation activity of this mutant receptor. In vivo studies with incremental doses of L-T3 demonstrated a reduced sensitivity to TH in the index case, in particular at the pituitary level where the thyrotrophs' activity was not completely inhibited even by 200 micrograms/day of L-T3. G251E mutation represents the fourth mutation described up to now in exon 8 of hTR beta among the subjects affected by RTH. A third cluster of mutations of the c-erbA beta gene located proximally with respect to the other two so far described begins to emerge in RTH patients.

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