RIVOLTA Carina Marcela
Defects in protein folding in congenital hypothyroidism.
TARGOVNIK, HM; SCHEPS, KAREN; RIVOLTA, CARINA M.
JOURNAL OF MOLECULAR ENDOCRINOLOGY
Lugar: Bristol; Año: 2020 vol. 501
Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the mostcommon preventable causes of both cognitive and motor deficits. CH is a heterogeneous group of thyroid disordersin which inadequate production of thyroid hormone occurs due to defects in proteins involved in thegland 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, hypoplasiaor ectopia of thyroid gland. Nevertheless, the etiology of the dysembryogenesis remains unknown formost cases. In contrast, the majority of patients with dyshormonogenesis has been linked to mutations in theSLC5A5, SLC26A4, SLC26A7, TPO, DUOX1, DUOX2, DUOXA1, DUOXA2, IYD or TG genes, which usually originategoiter.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, cysteineresidues or glycosylation sites, affecting the maturation of nascent proteins that go through the secretorypathway. Consequently, misfolded proteins are permanently entrapped in the endoplasmic reticulum (ER) andare 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 developmentof this disease remain to be elucidated. The continuous study of thyroid gene mutations with the applicationof new technologies will be useful for the understanding of the intrinsic mechanisms related to CH. Inthis review we summarize the present status of knowledge on the disorders in the protein folding caused bythyroid genes mutations.