García Marta, González de Buitrago Jesús, Jiménez-Rosés Mireia, Pardo Leonardo, Hinkle Patricia M, Moreno José C
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics, La Paz University Hospital, Autonomous University of Madrid, 28046 Madrid, Spain.
Department of Pediatrics, San Pedro de Alcántara Hospital, 10003 Cáceres, Spain.
J Clin Endocrinol Metab. 2017 Jul 1;102(7):2433-2442. doi: 10.1210/jc.2016-3977.
Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (TRH) receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood.
Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms.
All family members were phenotyped with thyroid hormone profiles, pituitary magnetic resonance imaging, TRH tests, and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB, and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling.
A homozygous missense mutation in TRHR (c.392T > C; p.I131T) was identified in an 8-year-old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; -0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq.
A unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.
中枢性先天性甲状腺功能减退症（CCH）是一种诊断不足的疾病，其特征是促甲状腺激素（TSH）分泌和生物活性不足，导致甲状腺激素合成减少。促甲状腺激素释放激素（TRH）受体（TRHR）缺陷是罕见的隐性疾病，通常与偶然发现的CCH和儿童期身材矮小有关。
对一个患有中枢性甲状腺功能减退症的罗姆族近亲家庭进行临床和基因特征分析，并确定潜在的分子机制。
对所有家庭成员进行甲状腺激素谱、垂体磁共振成像、TRH试验以及其他垂体激素的动态试验等表型分析。对候选的TRH、TRHR、TSHB和IGSF1基因进行突变筛查。对突变的TRHR进行体外和分子模拟表征。
在一名8岁中度甲状腺功能减退症男孩（TSH：2.61 mIU/L，正常范围：0.27至4.2；游离甲状腺素：9.52 pmol/L，正常范围：10.9至25.7）中鉴定出TRHR基因的纯合错义突变（c.392T > C；p.I131T），该男孩超重（体重指数：20.4 kg/m²，p91）但身高正常（122 cm；-0.58标准差）。他的母亲、两个兄弟和祖母为该突变的杂合子，伴有孤立性促甲状腺激素血症（TSH：4.3至8 mIU/L）。TRHR细胞内环2中的I131T突变降低了TRH亲和力，并增加了信号传导的半数最大有效浓度。TRHR-Gq复合物的模型预测该突变破坏了受体与由Gq形成的疏水口袋之间的相互作用。
在一个近亲家庭中鉴定出的独特错义TRHR缺陷与纯合子的中枢性甲状腺功能减退症和杂合子的促甲状腺激素血症有关，提示TSH代偿性升高但生物活性降低。I131T突变降低了TRH结合以及TRHR-Gq偶联和信号传导。
