title: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.
abstract: The paired-like homeobox gene expressed in embryonic stem cells Hesx1/HESX1 encodes a developmental repressor and is expressed in early development in a region fated to form the forebrain, with subsequent localization to Rathke's pouch, the primordium of the anterior pituitary gland. Mutations within the gene have been associated with septo-optic dysplasia, a constellation of phenotypes including eye, forebrain, and pituitary abnormalities, or milder degrees of hypopituitarism. We identified a novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology repressor domain (eh1) of HESX1, the first, to our knowledge, to be described in humans, in a girl with evolving combined pituitary hormone deficiency born to consanguineous parents. Neuroimaging revealed a thin pituitary stalk with anterior pituitary hypoplasia and an ectopic posterior pituitary, but no midline or optic nerve abnormalities. This I26T mutation did not affect the DNA-binding ability of HESX1 but led to an impaired ability to recruit the mammalian Groucho homolog/Transducin-like enhancer of split-1 (Gro/TLE1), a crucial corepressor for HESX1, thereby leading to partial loss of repression. Thus, the novel pituitary phenotype highlighted here appears to be a specific consequence of the inability of HESX1 to recruit Groucho-related corepressors, suggesting that other molecular mechanisms govern HESX1 function in the forebrain.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, Disciplina de Endocrinologia, Hospital das Clinicas de Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Luciani R
authors.initials: LR
authors.lastname: Carvalho
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Woods
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Nathalie
authors.initials: N
authors.lastname: Marcal
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Zamparini
authors.forename: Stefano
authors.initials: S
authors.lastname: Stifani
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Brickman
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins; D002675:Child, Preschool; D056970:Co-Repressor Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D007018:Hypopituitarism / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D010907:Pituitary Hormones / Q000172:deficiency; D012097:Repressor Proteins / Q000502:physiology*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D019382:Human Growth Hormone; D009687:Nuclear Proteins; D010907:Pituitary Hormones; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489736:HESX1 protein, human; C489734:Hes1 protein, mouse; C489733:Hesx1 protein, mouse; C499043:TLE1 protein, human; C091023:gro protein, Drosophila; C078493:HES1 protein, human