A family with a novel TSH receptor activating germline mutation (p.Ala485Val)

Abstract

Autosomal dominant nonautoimmune hyperthyroidism (ADNAH) is caused by gain of function mutations in the TSH receptor (TSHr) gene and characterized by toxic thyroid hyperplasia with a variable age of onset in the absence of thyroid antibodies and clinical symptoms of autoimmune thyroid disease in at least two generations. We report here a Turkish family with a novel TSHr gene mutation with distinct features all consistent with ADNAH. Thyroid function tests of the proband were as follows: free T3: 13.1 pg/ml (N: 1.8-4.6); free T4: 5.1 ng/dl (N: 0.9-1.7); TSH: 0.01 microIU/ml (N: 0.2-4.2); and TSH receptor antibody: 2 IU/ml (N: 0-10). A heterozygous missense mutation in exon 10 of the TSHr gene (c.1454C>T) resulting in the substitution of valine for alanine at codon 485 (p.Ala485Val) was found in the father and his son and daughter. This mutation had arisen de novo in the father. Functional studies of the novel TSHr germline mutation demonstrated a higher constitutive activation of adenyl cyclase than wild type without any effect on phospholipase C activity. In conclusion, our data indicate that gain of function germline mutations in the TSHr gene should be investigated in families with members suffering from thyrotoxicosis and progressive growth of goiter, but without clinical and biochemical evidence of autoimmune thyroid disease. In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

“…Therefore, our in vitro data show that the genotype alone could not explain the phenotypic severity of our familial cases with the M453T mutation. As suggested previously, other genetic and/or environmental factors are likely to influence the phenotype of nonautoimmune hyperthyroidism (10,11,18,19).…”

“…To date, ~30 constitutively activating TSHR mutations have been reported in nonautoimmune hyperthyroidism (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(15)(16)(17)(18)(19). Most of the activating mutations are present in TMD 1, 2, 3, and 5.…”

“…First, regarding goiter, its onset is variable even in cases and families harboring the same mutations of TSHR (10,11,16,18,19). In some patients, a goiter develops before the onset of clinical findings of hyperthyroidism (15); however, in other patients, the manifestation of hyperthyroidism precedes the onset of goiter (7,8,11,12,16).…”

“…Activating germline mutations of TSHR cause nonautoimmune sporadic congenital hyperthyroidism or familial nonautoimmune hyperthyroidism (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). To date, gain-of-function mutations in TMD 1, 2, 3, 5, 6, and 7 and in the ECD have been reported (4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

“…Obviously, this denomination is relatively inappropriate because these neomutants if properly treated would be able to transmit the disease to their descendants. This is clearly demonstrated in three families (23,35,36) where the less severe mutations led to a delayed diagnosis. The early age of clinical manifestation indicates a more severe phenotype, presumably related to a higher activation of the receptor.…”