Koulouri O, Nicholas A K, Schoenmakers E, Mokrosinski J, Lane F, Cole T, Kirk J, Farooqi I S, Chatterjee V K, Gurnell M, Schoenmakers N
Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
J Clin Endocrinol Metab. 2016 Mar;101(3):847-51. doi: 10.1210/jc.2015-3916. Epub 2016 Jan 6.
Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH β subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene.
A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2.
Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.
孤立性中枢性先天性甲状腺功能减退症（CCH）较为罕见，在英国基于促甲状腺激素（TSH）的先天性甲状腺功能减退症（CH）筛查项目中易被漏诊。因此，基因鉴定有助于家族性病例的诊断和治疗。已确认的病因包括促甲状腺激素β亚基（TSHB）和免疫球蛋白超家族成员1（IGSF1）突变，此前仅有两篇关于促甲状腺激素释放激素受体（TRHR）基因双等位基因、高度破坏性突变的报道。
一名出现新生儿黄疸持续时间延长的女婴被发现患有孤立性CCH，促甲状腺激素水平为2.2 mU/L（参考范围0.4 - 3.5），游离甲状腺素水平为7.9 pmol/L（0.61 ng/dL）（参考范围10.7 - 21.8 pmol/L）。由于TSHB或IGSF1突变通常与严重或X连锁的CCH相关，因此对TRHR进行了测序，并鉴定出一个纯合突变（p.P81R），该突变将精氨酸替代了跨膜螺旋2中一个高度保守的脯氨酸残基。功能研究表明突变型TRHR在细胞膜上的表达和定位正常；然而，其结合放射性标记的促甲状腺激素释放激素并通过Gqα信号转导的能力明显受损，这可能是由于跨膜螺旋2的结构扭曲所致。
此前报道的两个双等位基因、高度破坏性（无义突变；R17*，框内缺失和单氨基酸替代；p.[S115 - T117del；A118T]）TRHR突变与CCH相关；然而，我们描述了首例与该表型相关的有害错义TRHR缺陷。重要的是，突变氨基酸（脯氨酸81）的位置突出了第二个跨膜螺旋在介导激素结合和受体激活中的功能重要性。未来对其他自然发生的TRHR突变的鉴定可能会为促甲状腺激素释放激素受体的配体结合和激活的分子基础提供重要见解，目前对这方面的了解仍然很少。
