Defects in protein folding in congenital hypothyroidism

Abstract

Primary congenital hypothyroidism (CH) is the most commonendocrine disease in children and one of the most common preventablecauses of both cognitive and motor deficits. CH is a heterogeneous groupof thyroid disorders in which inadequate production of thyroid hormoneoccurs due to defects in proteins involved in the gland organogenesis(dysembryogenesis) or in multiple steps of thyroid hormone biosynthesis(dyshormonogenesis). Dysembryogenesis is associated with genesresponsible for the development or growth of thyroid cells: such as NKX2-1, FOXE1, PAX8, NKX2-5, TSHR, TBX1, CDCA8, HOXD3 and HOXB3 resulting inagenesis, hypoplasia or ectopia of thyroid gland. Nevertheless, theetiology of the dysembryogenesis remains unknown for most cases. Incontrast, the majority of patients with dyshormonogenesis has been linkedto 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 sofar, including missense, nonsense, in-frame deletion and splice-sitevariations. Many of these mutations are implicated in specific domains,cysteine residues or glycosylation sites, affecting the maturation ofnascent 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 bythe ER- associated degradation (ERAD) machinery.Despite of all these remarkable advances in the field of the CHpathogenesis, several points on the development of this disease remain tobe elucidated. The continuous study of thyroid gene mutations with theapplication of new technologies will be useful for the understanding ofthe intrinsic mechanisms related to CH. In this review we summarize thepresent status of knowledge on the disorders in the protein foldingcaused by thyroid genes mutations.