title: Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development.
abstract: The pathophysiology of combined pituitary hormone deficiency (CPHD) is just beginning to be elucidated, with mutations in genes encoding transcription factors expressed at different stages of pituitary development. Among them, the two closely related genes, LHX3 and LHX4, are believed to share redundant biological properties. The patients with a LHX3 mutation display a CPHD phenotype, associated with a rigid cervical spine. This latter feature, not reported in Lhx3-/- and Lhx4-/- mice nor in patients with a LHX4 defect, prompted us to study the molecular consequences of a previously identified LHX3 23-bp deletion and to determine the LHX3 and LHX4 expression patterns during early human development. This deletion, which results in the skipping of one coding exon, would lead to a protein with no transcriptional capability. Using in situ hybridization, we show that LHX3 and LHX4 are expressed in the developing human pituitary and along the rostro-caudal length of the spinal cord; here, both transcripts are detected in the ventral part giving rise to motorneurons and interneurons. However, whereas LHX3 is expressed at all stages studied, LHX4 expression is transient, and, at 6 weeks of development, is stronger at the caudal than at the cervical level.
authors.affiliation: Génétique Moléculaire et Physiopathologie, INSERM U468, Hôpital Henri Mondor, Créteil 94010, France.
authors.forename: M-L
authors.initials: ML
authors.lastname: Sobrier
authors.forename: T
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: I
authors.initials: I
authors.lastname: Netchine
authors.forename: F
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: M
authors.initials: M
authors.lastname: Vekemans
authors.forename: S
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010902:Pituitary Gland / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D010907:Pituitary Hormones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D010907:Pituitary Hormones; D014157:Transcription Factors