Enzo Cohen1,2, Mohamad Maghnie3, Nathalie Collot4, Juliane Leger5, Florence Dastot4, Michel Polak6, Sophie Rose4, Philippe Touraine7, Philippe Duquesnoy2, Maïté Tauber8, Bruno Copin2,4, Anne-Marie Bertrand9, Frederic Brioude10, Daniela Larizza11, Thomas Edouard8, Laura González Briceño6, Irène Netchine10, Isabelle Oliver-Petit8, Marie-Laure Sobrier2, Serge Amselem1,2,4, Marie Legendre2,4. 1. Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Unité Mixte de Recherche S933, F-75012, Paris, France. 2. INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France. 3. Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genoa, I-16147, Genoa, Italy. 4. Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France. 5. Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service d'Endocrinologie Pédiatrique, F-75019, Paris, France. 6. Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Service d'Endocrinologie Pédiatrique, F-75015, Paris, France. 7. Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Service d'Endocrinologie Pédiatrique, F-75013, Paris, France. 8. Centre Hospitalier Universitaire de Toulouse, Hôpital des Enfants, Service d'Endocrinologie et Génétique, F-70000, Toulouse, France. 9. Centre Hospitalier Universitaire de Besançon, Service de Pédiatrie Endocrinologie, F-25000, Besançon, France. 10. Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France. 11. Pediatric Endocrinology Unit, Department of Maternal and Children's Health, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Pavia and Department of Internal Medicine, University of Pavia, I-27100, Pavia, Italy.
Abstract
Context: LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective: The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results: We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion: This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.
Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective: The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results: We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221GlnLHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion: This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.
Authors: Youn Hee Jee; Mariam Gangat; Olga Yeliosof; Adrian G Temnycky; Selena Vanapruks; Philip Whalen; Evgenia Gourgari; Cortney Bleach; Christine H Yu; Ian Marshall; Jack A Yanovski; Kathleen Link; Svetlana Ten; Jeffrey Baron; Sally Radovick Journal: Front Genet Date: 2021-08-11 Impact factor: 4.599
Authors: Bartlomiej Budny; Tomasz Zemojtel; Malgorzata Kaluzna; Pawel Gut; Marek Niedziela; Monika Obara-Moszynska; Barbara Rabska-Pietrzak; Katarzyna Karmelita-Katulska; Marek Stajgis; Urszula Ambroziak; Tomasz Bednarczuk; Elzbieta Wrotkowska; Ewelina Bukowska-Olech; Aleksander Jamsheer; Marek Ruchala; Katarzyna Ziemnicka Journal: Front Endocrinol (Lausanne) Date: 2020-06-16 Impact factor: 5.555
Authors: Anna Szeliga; Michal Kunicki; Marzena Maciejewska-Jeske; Natalia Rzewuska; Anna Kostrzak; Blazej Meczekalski; Gregory Bala; Roman Smolarczyk; Eli Y Adashi Journal: Int J Mol Sci Date: 2021-12-08 Impact factor: 5.923