title: A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Endocrinology, Hôpital de la Timone, 264 rue St Pierre cedex 5, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Castinetti
authors.forename: A
authors.initials: A
authors.lastname: Saveanu
authors.forename: R
authors.initials: R
authors.lastname: Reynaud
authors.forename: M H
authors.initials: MH
authors.lastname: Quentien
authors.forename: A
authors.initials: A
authors.lastname: Buffin
authors.forename: R
authors.initials: R
authors.lastname: Brauner
authors.forename: N
authors.initials: N
authors.lastname: Kaffel
authors.forename: F
authors.initials: F
authors.lastname: Albarel
authors.forename: A M
authors.initials: AM
authors.lastname: Guedj
authors.forename: M
authors.initials: M
authors.lastname: El Kholy
authors.forename: M
authors.initials: M
authors.lastname: Amin
authors.forename: A
authors.initials: A
authors.lastname: Enjalbert
authors.forename: A
authors.initials: A
authors.lastname: Barlier
authors.forename: T
authors.initials: T
authors.lastname: Brue
mesh_terms: D000328:Adult; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital / Q000235:genetics*; D007438:Introns; D060850:LIM-Homeodomain Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors