Tiziana de Filippis1, Federica Marelli1, Gabriella Nebbia1, Patrizia Porazzi1, Sabrina Corbetta1, Laura Fugazzola1, Roberto Gastaldi1, Maria Cristina Vigone1, Roberta Biffanti1, Daniela Frizziero1, Luana Mandarà1, Paolo Prontera1, Mariacarolina Salerno1, Mohamad Maghnie1, Natascia Tiso1, Giorgio Radetti1, Giovanna Weber1, Luca Persani1. 1. Laboratorio 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.
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 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.
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 ALGS1patients. 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 ALGS1patients, 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 ALGS1patients. CONCLUSIONS: clinical and experimental data indicate that ALGS1patients 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.