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JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects
Tiziana de Filippis1, Federica Marelli1, Gabriella Nebbia1
1Laboratorio di Ricerche Endocrino-Metaboliche (T.d.F., F.M., P.Po., L.P.), Istituto di Ricevero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, 20149 Milano, Italy; Clinica Pediatrica De Marchi (G.N.) and Unità di Endocrinologia (L.F.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Dipartimento di Fisiopatologia Medica e Chirurgica e dei Trapianti (L.F.), Università degli Studi di Milano; and Dipartimento di Scienze Cliniche e di Comunità (L.P.), Università di Milano, 20122 Milano, Italy; Unità di Endocrinologia (S.C.), IRCCS Policlinico San Donato, 20097 San Donato Milanese, Milano, Italy; Dipartimento di Scienze Biomediche per la Salute (S.C.), Università degli Studi di Milano, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Milano, Italy; Dipartimento di Pediatria (R.G., M.M.), IRCCS Giannina Gaslini, Università di Genova, 16148 Genova, Italy; Dipartimento di Pediatria (M.C.V., G.E.), IRCCS Istituto San Raffaele, Università Vita-Salute San Raffaele, 20132 Milano, Italy; Dipartimento di Scienze Cardiache, Vascolari e Toraciche (R.B.), Università di Padova, 35128 Padova, Italy; Unità di Genetica Clinica ed Epidemiologica (D.F.), Università degli Studi-Azienda Ospedaliera di Padova, 35128 Padova, Italy; Unità di Genetica Medica (L.M.), Ospedale Maria Paternò Arezzo, 97100 Ragusa, Italy; Centro di Riferimento Regionale di Genetica Medica (P.Pr.), Azienda Ospedaliera-Universitaria di Perugia, 06156 Perugia, Italy; Dipartimento di Scienze Mediche Traslazionali (M.S.), Università degli Studi Federico II, 80131 Napoli, Italy; Dipartimento di Biologia (N.T.), Università di Padova, 35128 Padova, Italy; and Divisione Pediatrica (G.R.), Ospedale Regionale di Bolzano, 39100 Bolzano, Italy.
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.
Insights
Genetic variations in JAG1 are linked to congenital hypothyroidism (CH) and Alagille syndrome type 1 (ALGS1). These JAG1 variants can cause nonautoimmune hypothyroidism and thyroid defects in patients.
Area of Science:
- Endocrinology
- Genetics
- Developmental Biology
Background:
- The causes of congenital hypothyroidism (CH) remain largely unknown.
- Previous studies linked Notch pathway disruptions and jagged1 gene (JAG1) knockdown to hypothyroidism in zebrafish.
- JAG1 variants are associated with Alagille syndrome type 1 (ALGS1), a disorder with variable symptoms.
Purpose of the Study:
- To investigate the role of JAG1 variants in congenital thyroid disorders.
- To determine the frequency of unexplained hypothyroidism in Alagille syndrome patients.
Main Methods:
- Recruited 21 Alagille syndrome patients and 100 congenital hypothyroidism patients.
- Analyzed JAG1 variants in vitro and in zebrafish models.
- Conducted bioassays and zebrafish rescue experiments.
Main Results:
- Identified nonautoimmune hypothyroidism in 6/21 Alagille syndrome patients, with 2 showing thyroid hypoplasia.
- Found JAG1 variants in 4/100 congenital hypothyroidism cases, associated with thyroid dysgenesis and cardiac malformations.
- Demonstrated that identified JAG1 variants exhibit loss-of-function, and JAG1 knockdown in zebrafish causes thyroid defects.
Conclusions:
- Alagille syndrome patients face a higher risk of nonautoimmune hypothyroidism.
- JAG1 gene variations contribute to the development of congenital thyroid defects, including congenital hypothyroidism.
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