Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients.
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.



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.



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.



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.



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.
Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Unité Mixte de Recherche S933, F-75012, Paris, France.|INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France.
Enzo
E
Cohen
Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genoa, I-16147, Genoa, Italy.
Mohamad
M
Maghnie
Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France.
Nathalie
N
Collot
Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service d'Endocrinologie Pédiatrique, F-75019, Paris, France.
Juliane
J
Leger
Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France.
Florence
F
Dastot
Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Service d'Endocrinologie Pédiatrique, F-75015, Paris, France.
Michel
M
Polak
Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France.
Sophie
S
Rose
Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Service d'Endocrinologie Pédiatrique, F-75013, Paris, France.
Philippe
P
Touraine
INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France.
Philippe
P
Duquesnoy
Centre Hospitalier Universitaire de Toulouse, Hôpital des Enfants, Service d'Endocrinologie et Génétique, F-70000, Toulouse, France.
Maïté
M
Tauber
INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France.
Bruno
B
Copin
Centre Hospitalier Universitaire de Besançon, Service de Pédiatrie Endocrinologie, F-25000, Besançon, France.
Anne-Marie
AM
Bertrand
Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.
Frederic
F
Brioude
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.
Daniela
D
Larizza
Centre Hospitalier Universitaire de Toulouse, Hôpital des Enfants, Service d'Endocrinologie et Génétique, F-70000, Toulouse, France.
Thomas
T
Edouard
Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Service d'Endocrinologie Pédiatrique, F-75015, Paris, France.
Laura
L
González Briceño
Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France.
Irène
I
Netchine
Centre Hospitalier Universitaire de Toulouse, Hôpital des Enfants, Service d'Endocrinologie et Génétique, F-70000, Toulouse, France.
Isabelle
I
Oliver-Petit
INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France.
Marie-Laure
ML
Sobrier
Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Unité Mixte de Recherche S933, F-75012, Paris, France.|INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France.
Serge
S
Amselem
INSERM, Unité Mixte de Recherche S933, F-75012, Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, F-75012, Paris, France.
Marie
M
Legendre
D000293:Adolescent; D000595:Amino Acid Sequence; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D047468:Immunoprecipitation; D007223:Infant; D007231:Infant, Newborn; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*
D015415:Biomarkers; C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors