title: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.
abstract: Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.
authors.affiliation: [1] Laboratoire de Génétique et de Physiopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM) U.468, Hôpital Henri-Mondor, Créteil, France.
authors.forename: I
authors.initials: I
authors.lastname: Netchine
authors.forename: M L
authors.initials: ML
authors.lastname: Sobrier
authors.forename: H
authors.initials: H
authors.lastname: Krude
authors.forename: D
authors.initials: D
authors.lastname: Schnabel
authors.forename: M
authors.initials: M
authors.lastname: Maghnie
authors.forename: E
authors.initials: E
authors.lastname: Marcos
authors.forename: B
authors.initials: B
authors.lastname: Duriez
authors.forename: V
authors.initials: V
authors.lastname: Cacheux
authors.forename: A v
authors.initials: Av
authors.lastname: Moers
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: A
authors.initials: A
authors.lastname: Grüters
authors.forename: S
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D002574:Cervical Vertebrae / Q000002:abnormalities / Q000503:physiopathology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003001:Cloning, Molecular; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D020161:Physical Chromosome Mapping; D010903:Pituitary Gland, Anterior / Q000002:abnormalities / Q000503:physiopathology; D010908:Pituitary Hormones, Anterior / Q000032:analysis / Q000172:deficiency*; D012399:Rotation; D016415:Sequence Alignment; D017384:Sequence Deletion / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors
chemical_list: D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D010908:Pituitary Hormones, Anterior; D014157:Transcription Factors