A family with a novel TSH receptor activating germline mutation (p.Ala485Val) |
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Authors: | Sema Akcurin Doga Turkkahraman Carolyn Tysoe Sian Ellard Anne De Leener Gilbert Vassart Sabine Costagliola |
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Institution: | (1) Department of Pediatric Endocrinology, Akdeniz University Hospital, Antalya, Turkey;(2) Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK;(3) Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK;(4) I.R.I.B.H.M., Faculté de Médecine, Université Libre de Bruxelles (ULB), Brussels, Belgium |
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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 μIU/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. |
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Keywords: | TSH receptor Activating mutation Familial |
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