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 academicandpublic hospitals. TheJAG1variantswerestudied in vitroandin the zebrafish. Results:Wereport 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.

JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects / T. De Filippis, F. Marelli, G. Nebbia, P. Porazzi, S. Corbetta, L. Fugazzola, R. Gastaldi, M.C. Vigone, R. Biffanti, D. Frizziero, L. Mandarà, P. Prontera, M. Salerno, M. Maghnie, N. Tiso, G. Radetti, G. Weber, L. Persani. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 101:3(2016), pp. 861-870. [10.1210/jc.2015-3403]

JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects

F. Marelli
Secondo
;
P. Porazzi;S. Corbetta;L. Fugazzola;L. Persani
2016

Abstract

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 academicandpublic hospitals. TheJAG1variantswerestudied in vitroandin the zebrafish. Results:Wereport 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.
Alagille-syndrome; mouse model; hypothyroidism; mutatations; genetics; JAGGED1; zebrafish; diagnosis; ligand; TSH
Settore MED/13 - Endocrinologia
Settore MED/38 - Pediatria Generale e Specialistica
Article (author)
File in questo prodotto:
File Dimensione Formato  
JC-15-3403_R1 (1).pdf

accesso aperto

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 2.63 MB
Formato Adobe PDF
2.63 MB Adobe PDF Visualizza/Apri
jc%2E2015-3403.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 2.17 MB
Formato Adobe PDF
2.17 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/421793
Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 31
  • ???jsp.display-item.citation.isi??? 28
social impact