JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects

Context: The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille sy...

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Published in:	The journal of clinical endocrinology and metabolism Vol. 101; no. 3; pp. 861 - 870
Main Authors:	de Filippis, Tiziana, Marelli, Federica, Nebbia, Gabriella, Porazzi, Patrizia, Corbetta, Sabrina, Fugazzola, Laura, Gastaldi, Roberto, Vigone, Maria Cristina, Biffanti, Roberta, Frizziero, Daniela, Mandarà, Luana, Prontera, Paolo, Salerno, Mariacarolina, Maghnie, Mohamad, Tiso, Natascia, Radetti, Giorgio, Weber, Giovanna, Persani, Luca
Format:	Journal Article
Language:	English
Published:	United States Endocrine Society 01-03-2016 Copyright by The Endocrine Society
Subjects:	Adult Alagille Syndrome - genetics Animals Calcium-Binding Proteins - genetics Child Child, Preschool Computational Biology Female Fluorescent Antibody Technique Humans Intercellular Signaling Peptides and Proteins - genetics Jagged-1 Protein Male Membrane Proteins - genetics Serrate-Jagged Proteins Thyroid Dysgenesis - genetics Zebrafish Zebrafish Proteins
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Summary:	Context: The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. Objective: Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. Design, Settings, and Patients: A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. Results: We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. Conclusions: clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.
Bibliography:	This work was supported by the Italian Ministry of Health, Rome, Italy Grant RF-2010-2309484. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-972X 1945-7197
DOI:	10.1210/jc.2015-3403