|ZFIN ID: ZDB-PUB-160114-3|
JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects
de Filippis, T., Marelli, F., Nebbia, G., Porazzi, P., Corbetta, S., Fugazzola, L., Gastaldi, R., Vigone, M.C., Biffanti, R., Frizziero, D., Mandarà, L., Prontera, P., Salerno, M., Maghnie, M., Tiso, N., Radetti, G., Weber, G., Persani, L.
|Source:||The Journal of clinical endocrinology and metabolism 101(3): 861-70 (Journal)|
|Registered Authors:||Porazzi, Patrizia, Tiso, Natascia|
|PubMed:||26760175 Full text @ J. Clin. Endocrinol. Metab.|
de Filippis, T., Marelli, F., Nebbia, G., Porazzi, P., Corbetta, S., Fugazzola, L., Gastaldi, R., Vigone, M.C., Biffanti, R., Frizziero, D., Mandarà, L., Prontera, P., Salerno, M., Maghnie, M., Tiso, N., Radetti, G., Weber, G., Persani, L. (2016) JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects. The Journal of clinical endocrinology and metabolism. 101(3):861-70.
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, 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 non-autoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found two 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 non-autoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.