Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the most common preventable causes of both cognitive and motor deficits. CH is a heterogeneous group of thyroid disorders in which inadequate production of thyroid hormone occurs due to defects in proteins involved in the gland organogenesis (dysembryogenesis) or in multiple steps of thyroid hormone biosynthesis (dyshormonogenesis). Dysembryogenesis is associated with genes responsible for the development or growth of thyroid cells: such as NKX2-1, FOXE1, PAX8, NKX2-5, TSHR, TBX1, CDCA8, HOXD3 and HOXB3 resulting in agenesis, hypoplasia or ectopia of thyroid gland. Nevertheless, the etiology of the dysembryogenesis remains unknown for most cases. In contrast, the majority of patients with dyshormonogenesis has been linked to mutations in the SLC5A5, SLC26A4, SLC26A7, TPO, DUOX1, DUOX2, DUOXA1, DUOXA2, IYD or TG genes, which usually originate goiter. About 800 genetic mutations have been reported to cause CH in patients so far, including missense, nonsense, in-frame deletion and splice-site variations. Many of these mutations are implicated in specific domains, cysteine residues or glycosylation sites, affecting the maturation of nascent proteins that go through the secretory pathway. Consequently, misfolded proteins are permanently entrapped in the endoplasmic reticulum (ER) and are translocated to the cytosol for proteasomal degradation by the ER-associated degradation (ERAD) machinery. Despite of all these remarkable advances in the field of the CH pathogenesis, several points on the development of this disease remain to be elucidated. The continuous study of thyroid gene mutations with the application of new technologies will be useful for the understanding of the intrinsic mechanisms related to CH. In this review we summarize the present status of knowledge on the disorders in the protein folding caused by thyroid genes mutations.

中文翻译：

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先天性甲状腺功能减退症中蛋白质折叠的缺陷。

原发性先天性甲状腺功能减退症（CH）是儿童中最常见的内分泌疾病，也是认知和运动功能障碍的最常见可预防原因之一。CH是甲状腺疾病的异质性组，其中由于参与腺体器官发生（膜胚发生）或甲状腺激素生物合成的多个步骤（分泌异常）的蛋白质缺陷而导致甲状腺激素产生不足。胚发生异常与负责甲状腺细胞发育或生长的基因有关：例如NKX2-1，FOXE1，PAX8，NKX2-5，TSHR，TBX1，CDCA8，HOXD3和HOXB3，导致甲状腺发育不全，发育不全或异位。然而，在大多数情况下，胚芽发育的病因仍是未知的。相比之下，大多数患有肌营养不良症的患者都与SLC5A5中的突变有关，SLC26A4，SLC26A7，TPO，DUOX1，DUOX2，DUOXA1，DUOXA2，IYD或TG基因通常起源于甲状腺肿。迄今为止，据报道约有800个基因突变可引起患者CH，包括错义，无义，框内缺失和剪接位点变异。这些突变中的许多都与特定结构域，半胱氨酸残基或糖基化位点有关，从而影响通过分泌途径的新生蛋白质的成熟。因此，错误折叠的蛋白质被永久地包埋在内质网（ER）中，并通过ER相关降解（ERAD）机器转移到胞质溶胶中进行蛋白酶体降解。尽管在CH发病机制领域取得了所有这些显着进步，但关于该病发展的几点仍待阐明。随着新技术的应用，对甲状腺基因突变的持续研究将有助于了解与CH相关的内在机制。在这篇综述中，我们总结了由甲状腺基因突变引起的蛋白质折叠异常的知识的现状。