The Coexistence of a Novel Inactivating Mutant Thyrotropin Receptor Allele with Two Thyroid Peroxidase Mutations: A Genotype-Phenotype Correlation
The Coexistence of a Novel Inactivating Mutant Thyrotropin Receptor Allele with Two Thyroid Peroxidase Mutations: A Genotype-Phenotype Correlation
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DOI：
10.1210/jc.2011-0127
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发表时间：
2011-06-01
影响因子：
5.8
通讯作者：
Refetoff, Samuel
中科院分区：
文献类型：
--
作者：
Sriphrapradang, Chutintorn;Tenenbaum-Rakover, Yardena;Refetoff, Samuel
背景：TSH 受体 (TSHR) 和甲状腺过氧化物酶 (TPO) 基因突变独立发生。这是它们在同一个体中共存的第一份报告。目的：该研究的目的是评估当两个基因的突变单独或同时存在于同一个体中时的基因型-表型相关性。患者和方法：来自阿拉伯家族的 30 名受试者接受了突变 TSHR 的临床调查和分子研究。结果：鉴定出一种新的突变 TSHR，涉及同一等位基因上三个位点的 4 个核苷酸，c.267G>T (L89L)、c.269/270AG>CT (Q90P) 和 c.790C>T (P264S)。此外，还鉴定出两种已知的 TPO 基因突变：G493S 和 R540X。突变 TSHR 等位基因的 13 个杂合子患有轻度高促甲状腺素血症。在其中九篇论文中，一个等位基因中 TPO 突变的共存并没有放大高甲状腺激素血症。 TSHR 突变的纯合子和 TPO 突变的复合杂合子表现出明显的甲状腺功能减退症。体外研究表明，Q90P 的功能丧失程度比 P264S 的程度要小，而 Q90P/P264STSHR 突变体的功能丧失程度要小，后者在所研究的受试者中表达。这两种可互换使用的 WT TSHR 载体 L87 和 V87 虽然功能相同，但在存在 Q90P 突变的情况下在结构和功能上有所不同。结论：在近亲亲属个体中单独和一起鉴定了 TSHR 和 TPO 基因突变。 TSHR 纯合子和 TPO 突变复合杂合子均为甲状腺功能减退。突变型 TSHR 等位基因杂合子的轻度高促甲状腺素血症并未因一个等位基因中 TPO 缺陷的共存而加剧。 （临床内分泌代谢杂志 96：E1001-E1006，2011）
Context: TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals.Objectives: The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual.Patients and Methods: Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs.Results: A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264STSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation.Conclusions: TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele. (J Clin Endocrinol Metab 96: E1001-E1006, 2011)