A heritable point mutation in an extracellular domain of the TSH receptor involved in the interaction with Graves' immunoglobulins.

The TSH receptor (TSHR) is the central antigen in Graves' disease. Variant receptor proteins, arising from mutations in the TSHR gene, may play a role in the pathogenesis of the disease. Therefore, we analysed the TSHR from a 38-year-old patient affected with autoimmune hyperthyroidism, diffuse goitre and ophthalmopathy. Reverse transcription PCR and DNA amplification followed by DNA sequencing revealed a point mutation (C-->A) at cDNA position 253 in one of two alleles. This leads to the replacement of a proline (CCC) by threonine (ACC) at amino acid position 52 of the predicted receptor protein. Secondary structure predictions indicated a major change of protein structure as a result of the mutation. By using allele-specific PCR, we were able to show that this mutation is heritable. Screening of 50 random individuals revealed that four of them also carried this mutation in the heterozygous state. This study shows the presence of different forms of the TSHR gene in the population. The mutation, which is in a portion of the receptor apparently involved in binding of Graves' immunoglobulins, is discussed as to its possible pathophysiological role in autoimmune hyperthyroidism.