{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:12:28Z","timestamp":1791353548124,"version":"4.3.1"},"reference-count":36,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design and Patients:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G&amp;gt;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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>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 \u223c1.4% in the 417 probands tested.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jc.2016-3158","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T14:01:35Z","timestamp":1478527295000},"page":"290-301","source":"Crossref","is-referenced-by-count":25,"title":["Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients"],"prefix":"10.1210","volume":"102","author":[{"given":"Enzo","family":"Cohen","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9s, Universit\u00e9 Pierre et Marie Curie, Universit\u00e9 Paris 06, Unit\u00e9 Mixte de Recherche S933, F-75012, Paris, France;"},{"name":"INSERM, Unit\u00e9 Mixte de Recherche S933, F-75012, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[{"name":"Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genoa, I-16147, Genoa, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Collot","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Trousseau, Service de G\u00e9n\u00e9tique et d\u2019Embryologie M\u00e9dicales, F-75012, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Leger","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Robert Debr\u00e9, Service d\u2019Endocrinologie P\u00e9diatrique, F-75019, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Dastot","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Trousseau, Service de G\u00e9n\u00e9tique et d\u2019Embryologie M\u00e9dicales, F-75012, Paris, 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France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Besan\u00e7on, Service de P\u00e9diatrie Endocrinologie, F-25000, Besan\u00e7on, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Brioude","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Larizza","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Edouard","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Toulouse, H\u00f4pital des Enfants, Service d\u2019Endocrinologie et G\u00e9n\u00e9tique, F-70000, Toulouse, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gonz\u00e1lez Brice\u00f1o","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Necker, Service d\u2019Endocrinologie P\u00e9diatrique, F-75015, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ir\u00e8ne","family":"Netchine","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, 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