Camilot Marta, Teofoli Francesca, Gandini Alberto, Franceschi Roberto, Rapa Anna, Corrias Andrea, Bona Gianni, Radetti Giorgio, Tatò Luciano
Dipartimento Materno Infantile e di Biologia Genetica Sez. Pediatrica, University of Verona, Verona, Italy.
Clin Endocrinol (Oxf). 2005 Aug;63(2):146-51. doi: 10.1111/j.1365-2265.2005.02314.x.
TSH resistance ranges from overt nonautoimmune hypothyroidism to subclinical hypothyroidism, defined as mild hyperthyrotrophinaemia but a euthyroid state clinically. To date, 23 inactivating mutations of the TSH receptor (TSHR) gene have been proven responsible for the clinical condition, but an absence of mutations in the TSHR gene has been reported for several cases of TSH resistance as well. In this paper, we aimed to investigate the actual role of the TSHR gene in the development of both subclinical and congenital hypothyroidism.
14 hypothyroid newborns, 116 subclinical hypothyroid subjects and 120 healthy controls.
Through denaturing high performance liquid chromatography (DHPLC), we screened for mutations the TSHR gene (the proximal promoter, the exons and their flanking regions), and evaluated the association between serum TSH and functionally characterized alleles identified.
In the hypothyroid patients, one patient was heterozygous for a new missense variation, E34K, whereas two others patients were either homozygous or heterozygous for the P162A substitution. In the subclinical hypothyroid subjects, we detected only heterozygous substitutions: they are mostly new (123-124insTGCA, P27T, R46P, 555-561delTATTCTT, D403N, W488R, M527T), while six correspond to already published mutations (P162A, R109Q, L252P and three C41S). We only focused on those mutations that had been functionally characterized in vitro, and in whom serum TSH was available from family members.
A single grossly mutated allele (such as C41S or 555-561del) invariably leads to a condition of subclinical hypothyroidism, whereas in case of heterozygous carriers of mutations partially affecting the receptor function (such as P162A or L252P), a remarkable variable expressivity was detected among individuals belonging to different generations.
促甲状腺激素（TSH）抵抗涵盖从明显的非自身免疫性甲状腺功能减退到亚临床甲状腺功能减退，后者定义为轻度促甲状腺激素血症但临床上甲状腺功能正常的状态。迄今为止，已证实TSH受体（TSHR）基因的23种失活突变与该临床病症有关，但也有几例TSH抵抗病例报告称TSHR基因未发生突变。在本文中，我们旨在研究TSHR基因在亚临床和先天性甲状腺功能减退症发生发展中的实际作用。
14例甲状腺功能减退新生儿、116例亚临床甲状腺功能减退受试者和120例健康对照者。
通过变性高效液相色谱法（DHPLC），我们筛查了TSHR基因（近端启动子、外显子及其侧翼区域）的突变，并评估了血清TSH与已鉴定的功能特征等位基因之间的关联。
在甲状腺功能减退患者中，1例患者为新的错义变异E34K杂合子，而另外2例患者为P162A替代的纯合子或杂合子。在亚临床甲状腺功能减退受试者中，我们仅检测到杂合子替代：它们大多是新的（123 - 124insTGCA、P27T、R46P、555 - 561delTATTCTT、D403N、W488R、M527T），而6种与已发表的突变（P162A、R109Q、L252P和三种C41S）相对应。我们仅关注那些在体外已进行功能特征鉴定且其家庭成员有血清TSH数据的突变。
单个严重突变的等位基因（如C41S或555 - 561del）总是导致亚临床甲状腺功能减退状态，而对于部分影响受体功能的突变杂合携带者（如P162A或L252P），在不同代的个体中检测到显著的可变表达。
