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

Tiziana de Filippis, Federica Marelli, Gabriella Nebbia, P. Porazzi, Sabrina Luigia Corbetta, Laura Fugazzola, R. Gastaldi, Maria Cristina Vigone, Roberta Biffanti, Daniela Frizziero, Luana Mandarà, P. Prontera, Maria Carolina Salerno, Mohamad Maghnie, N. Tiso, G. Radetti, Giovanna Weber, Luca Persani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)861-870
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume101
Issue number4
DOIs
Publication statusPublished - Mar 1 2016

Fingerprint

Alagille Syndrome
Congenital Hypothyroidism
Thyroid Gland
Defects
Zebrafish
Thyroid Dysgenesis
Bioassay
Phenotype
Genes
Ligands
Penetrance
Hypothyroidism
Biological Assay
Experiments

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects. / de Filippis, Tiziana; Marelli, Federica; Nebbia, Gabriella; Porazzi, P.; Corbetta, Sabrina Luigia; Fugazzola, Laura; Gastaldi, R.; Vigone, Maria Cristina; Biffanti, Roberta; Frizziero, Daniela; Mandarà, Luana; Prontera, P.; Salerno, Maria Carolina; Maghnie, Mohamad; Tiso, N.; Radetti, G.; Weber, Giovanna; Persani, Luca.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 101, No. 4, 01.03.2016, p. 861-870.

Research output: Contribution to journalArticle

de Filippis, T, Marelli, F, Nebbia, G, Porazzi, P, Corbetta, SL, Fugazzola, L, Gastaldi, R, Vigone, MC, Biffanti, R, Frizziero, D, Mandarà, L, Prontera, P, Salerno, MC, 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', Journal of Clinical Endocrinology and Metabolism, vol. 101, no. 4, pp. 861-870. https://doi.org/10.1210/jc.2015-3403
de Filippis, Tiziana ; Marelli, Federica ; Nebbia, Gabriella ; Porazzi, P. ; Corbetta, Sabrina Luigia ; Fugazzola, Laura ; Gastaldi, R. ; Vigone, Maria Cristina ; Biffanti, Roberta ; Frizziero, Daniela ; Mandarà, Luana ; Prontera, P. ; Salerno, Maria Carolina ; Maghnie, Mohamad ; Tiso, N. ; Radetti, G. ; Weber, Giovanna ; Persani, Luca. / JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects. In: Journal of Clinical Endocrinology and Metabolism. 2016 ; Vol. 101, No. 4. pp. 861-870.
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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.",
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T1 - JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects

AU - de Filippis, Tiziana

AU - Marelli, Federica

AU - Nebbia, Gabriella

AU - Porazzi, P.

AU - Corbetta, Sabrina Luigia

AU - Fugazzola, Laura

AU - Gastaldi, R.

AU - Vigone, Maria Cristina

AU - Biffanti, Roberta

AU - Frizziero, Daniela

AU - Mandarà, Luana

AU - Prontera, P.

AU - Salerno, Maria Carolina

AU - Maghnie, Mohamad

AU - Tiso, N.

AU - Radetti, G.

AU - Weber, Giovanna

AU - Persani, Luca

PY - 2016/3/1

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N2 - 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.

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