A genomic point mutation in the extracellular domain of the thyrotropin receptor in patients with Graves' ophthalmopathy

R. S. Bahn, C. M. Dutton, A. E. Heufelder, G. Sarkar

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Orbital and pretibial fibroblasts are targets of autoimmune attack in Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD). The fibroblast autoantigen involved in these peripheral manifestations of Graves' disease and the reason for the association of GO and PTD with hyperthyroidism are unknown. RNA encoding the full-length extracellular domain of the TSH receptor has been demonstrated in orbital and dermal fibroblasts from patients with GO and normal subjects, suggesting a possible antigenic link between fibroblasts and thyrocytes. RNA was isolated from cultured orbital, pretibial, and abdominal fibroblasts obtained from patients with severe GO (n = 22) and normal subjects (n = 5). RNA was reverse transcribed, and the resulting cDNA was amplified by the polymerase chain reaction, using primers spanning overlapping regions of the entire extracellular domain of the TSH receptor. Nucleotide sequence analysis showed an A for C substitution in the first position of codon 52 in 2 of the patients, both of whom had GO, PTD, and acropachy. Genomic DNA isolated from the 2 affected patients, and not from an additional 12 normal subjects, revealed the codon 52 mutation by direct sequencing and AciI restriction enzyme digestions. In conclusion, we have demonstrated the presence of a genomic point mutation, leading to a threonine for proline amino acid shift in the predicted peptide, in the extracellular domain of the TSH receptor in two patients with severe GO, PTD, acropachy, and high thyroid-stimulating immunoglobulin levels. RNA encoding this mutant product was demonstrated in the fibroblasts of these patients. We suggest that the TSH receptor may be an important fibroblast autoantigen in GO and PTD, and that this mutant form of the receptor may have unique immunogenic properties.

Original languageEnglish (US)
Pages (from-to)256-260
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume78
Issue number2
DOIs
StatePublished - Feb 1994

Fingerprint

Graves Ophthalmopathy
Thyrotropin Receptors
Fibroblasts
Point Mutation
RNA
Autoantigens
Codon
Thyroid-Stimulating Immunoglobulins
Polymerase chain reaction
Graves Disease
Hyperthyroidism
Threonine
Proline
Sequence Analysis
Digestion
Substitution reactions
Nucleotides
Complementary DNA
Association reactions
Amino Acids

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

A genomic point mutation in the extracellular domain of the thyrotropin receptor in patients with Graves' ophthalmopathy. / Bahn, R. S.; Dutton, C. M.; Heufelder, A. E.; Sarkar, G.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 78, No. 2, 02.1994, p. 256-260.

Research output: Contribution to journalArticle

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