ESPEYB17 3. Thyroid New genes (2 abstracts)
3.9. Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome
Li M , Nishio SY , Naruse C , Riddell M , Sapski S , Katsuno T , Hikita T , Mizapourshafiyi F , Smith FM , Cooper LT , Lee MG , Asano M , Boettger T , Krueger M , Wietelmann A , Graumann J , Day BW , Boyd AW , Offermanns S , Kitajiri SI , Usami SI & Nakayama M
To read the full abstract: Nat Commun. 2020;11:1343.
Li et al. describe a new genetic mechanism causing Pendred syndrome and extend evidence for an oligogenic origin of congenital hypothyroidism (CH). Autosomal recessive mutations in Pendrin (PDS/SCL26A4 ) were described in 1997 to cause Pendred syndrome [1]. However, over the years patients with either only heterozygous or even no mutation in PDS/SLC26A4 have been diagnosed with the full clinical picture of Pendred syndrome, including mild dyshormonogenetic hypothyroidism and severe deafness, suggesting alternative genetic origins.
In this elegant work, the authors identified mutations in the EPHA2 gene in patients with heterozygous PDS/SLC26A4 mutations. EPHA2 belongs to the Ephrin ligands involved in transmembrane protein localization processes and governing compartmentalization during epithelial development. By studying Epha2 knockout mice, the authors revealed disrupted epithelial development in the inner ear and in the thyroid with mislocalization of Pendrin in thyrocytes. These data are intriguing, as the classical difference between thyroid dysgenesis and thyroid dyshormonogenesis is challenged by the digenic inheritance of Pendred syndrome combining a functional defect of PDS/SLC26A4 with a structural defect of Pendrin localization caused by the second gene defect in EPHA2. It further extends the concept of digenic origin of CH to genes beyond transcription factors involved in thyroid development or enzymes crucial for thyroid hormone synthesis. Based on this concept and approach, further new genes are expected to be identified in CH patients.
Reference:
1. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997;17:411–422.
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ESPE Yearbook of Paediatric Endocrinology
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