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A Novel Dysfunctional LHX4 Mutation with High Phenotypical Variability in Patients with Hypopituitarism

Centre de Recherche en neurobiologie et neurophysiologie de Marseille (CRN2M) (F.C., A.S., R.R., M.H.Q., F.A., A.E., A.Ba., T.B.), Unité Mixte de Recherche 6231, Faculté de Médecine Nord, Centre National de la Recherche Scientifique, Université de la Méditerranée and Centre de Référence des déficits hypophysaires, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille, 13385 Marseille, France; Laboratoire de Biochimie-Biologie Moléculaire (A.S., A.E., A.Ba.), Hôpital Conception, 13005 Marseille, France; Service de Pédiatrie (A.Bu.), Centre Hospitalier Chambéry, 73000 Chambéry France; Université Paris-Descartes et Assistance Publique–Hôpitaux de Paris (R.B.), Hôpital Bicêtre, 94270 Le Kremlin Bicêtre, France; Service d’endocrinologie (N.K.), Centre Hospitalier Universitaire Hedi-Chaker, route El-Ain, 3029 Sfax, Tunisie; Service des Maladies Métaboliques et Endocriniennes (A.M.G.), Centre Hospitalier Universitaire de Nîmes, 30000 Nîmes France; Department of Paediatrics (M.E.K.), Ain Shams University, 11566 Cairo, Egypt; Department of Paediatrics (M.A.), Cairo University, 11566 Cairo, Egypt

Address all correspondence and requests for reprints to: Professor T. Brue, Department of Endocrinology, Hôpital de la Timone, 264 rue St Pierre, cedex 5, 13385 Marseille, France. E-mail: thierry.brue{at}mail.ap-hm.fr.

Context: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone deficiency.

Subjects and Methods: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations.

Results: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients’ phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters.

Conclusions: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.