Clinical characterization and genetic analysis of a large euthyroid family with the new TSH receptor germline mutation (N372T) and a hyperthyroid index patient with an additional somatic TSH receptor mutation (S281N) on the second TSH receptor allele

Familial autosomal dominant non-autoimmune hyperthyroidism is a rare disease caused by constitutively activating germline mutations of the TSH receptor (TSHR). Here we describe a large euthyroid family with a new germline mutation in TSHR ectodomain (ECD) where the only hyperthyroid family member also carried a somatic TSHR mutation in a large hot nodule. Mutation analysis of exons 9 and 10 of the TSHR gene from peripheral blood samples of the family members and the toxic thyroid nodule of the index patient was performed by denaturing gradient gel electrophoresis followed by direct sequencing.

A novel germline mutation N372T was found in a blood sample of a 53 year-old man with thyrotoxic storm. The mutation was also detected in six siblings and seven children of this patient which were all euthyroid. Under the conditions of iodine deficiency this N372T mutation induced diffuse goiters in the children up to the age of 20 which became progressively multinodular later in life beginning at the age of 22 years. Interestingly an additional somatic mutation (S281N) was identified in dominant toxic thyroid nodules of the index patient. Both mutations were located on different alleles of the TSHR gene. For both single mutants N372T and S281N and the coexpression of N372T/S281N, the basal cAMP level was increased compared to wild-type TSHR. Specific constitutive activity of S281N was higher than for coexpression of N372T/S281N and it was lowest in the N372T mutant.

Conclusion: We describe a third locus for constitutively activating mutations in the TSHR ECD. Whereas all previously reported patients with a TSHR germline mutation were hyperthyroid, iodine deficiency is the most likely reason why this is the first family with 13 euthyroid family members carrying a TSHR germline mutation. The index patient is also the first case with compound heterozygosity for two constitutively activating TSHR mutations (N372T, germline; S281N, somatic) in a hot nodule and being the most likely reason why this is the only family member with the N372T mutation with hyperthyroidism.