A family with a novel TSH receptor activating germline mutation (p.Ala485Val)
A family with a novel TSH receptor activating germline mutation (p.Ala485Val)
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DOI：
10.1007/s00431-007-0659-9
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发表时间：
2008-11-01
影响因子：
3.6
通讯作者：
Costagliola, Sabine
中科院分区：
文献类型：
--
作者：
Akcurin, Sema;Turkkahraman, Doga;Costagliola, Sabine
常染色体显性遗传非自身免疫性甲状腺功能亢进症（ADNAH）是由TSH受体（TSHr）基因的功能获得性突变引起的，其特征是毒性甲状腺增生，在缺乏甲状腺抗体的情况下具有不同的发病年龄，并且至少两代人具有自身免疫性甲状腺疾病的临床症状。我们在这里报告一个土耳其家庭与一个新的TSHr基因突变的独特功能都与ADNAH一致。先证者甲状腺功能检查结果如下：游离T3：13.1 pg/ml（N：1.8-4.6）;游离T4：5.1 ng/dl（N：0.9-1.7）; TSH：0.01 μ IU/ml（N：0.2-4.2）; TSH受体抗体：2 IU/ml（N：0-10）。在父亲及其儿子和女儿中发现了TSHr基因第10外显子的杂合错义突变（c.1454C > T），导致密码子485处的丙氨酸被缬氨酸取代（p.Ala485Val）。这种突变是在父亲身上重新出现的。新的TSHr种系突变的功能研究表明，一个更高的组成型激活腺苷酸环化酶比野生型没有任何影响磷脂酶C的活性。总之，我们的数据表明，获得的功能生殖系突变的TSHr基因应进行调查的家庭成员患有甲状腺毒症和甲状腺肿的进行性生长，但没有临床和生化证据的自身免疫性甲状腺疾病。此外，携带相同TSHr基因突变的患者可能在发病年龄、甲状腺功能亢进的严重程度和甲状腺生长方面表现出广泛的表型变异性。
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 mu IU/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.