hes1-protein--human and Hypopituitarism

Topics: Adrenocorticotropic Hormone; Animals; Basic Helix-Loop-Helix Transcription Factors; DNA-Binding Proteins; Fushi Tarazu Transcription Factors; Gonadotropins, Pituitary; Homeobox Protein PITX2; Homeodomain Proteins; Humans; Hypopituitarism; Mice; Mutation; Pituitary Diseases; Pituitary Gland, Anterior; Pituitary Hormones; T-Box Domain Proteins; Transcription Factor HES-1; Transcription Factor Pit-1; Transcription Factors

This review will address contributions of nuclear transcription factors to the embryologic development and definitive function of the anterior pituitary gland. The HESX1, PITX1, PITX2, PROP1 and POU1F1 genes are of particular interest because of their recognized or potential associations with human disease. Mutations of any of the first three genes produce complex disease phenotypes such as septo-optic dysplasia, Treacher Collins Franceschetti syndrome or Rieger syndrome that may include deficiency of one or more pituitary hormones. Mutations in PROP1 or POU1F1, or their mouse homologous, result in severe hypopituitarism as well as morphological abnormalities of the pituitary gland.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Disease Models, Animal; Genes, Homeobox; Homeobox Protein PITX2; Homeodomain Proteins; Humans; Hypopituitarism; Mice; Mice, Mutant Strains; Nuclear Proteins; Paired Box Transcription Factors; Phenotype; Pituitary Gland; Repressor Proteins; Transcription Factor HES-1; Transcription Factors

Basic and translational research achievements over the past 2 decades have disclosed the molecular mechanisms underlying several genetic forms of hypopituitarism. Disorders that are limited to the hypothalamic, pituitary, GH axis are caused by mutations in individual components of that axis. Disorders involving GH and one or more additional pituitary hormones are caused by mutations in the homeodomain transcription factors that direct embryological development of the anterior pituitary gland. Pit-1 has a POU-specific and a POU-homeo DNA-binding domain. The phenotype produced by mutations in the PIT1 gene involves deficiencies of GH, PRL, and TSH. Pituitary glands are either small or normally sized. The PROP1 gene encodes a transcription factor with a single paired-like DNA-binding domain. Persons with inactivating mutations in PROP1 have deficiencies of LH and FSH, as well as GH, PRL, and TSH. Their pituitary glands may be small, normally sized, or extremely large and show suprasellar extension. Pituitary degeneration may produce acquired deficiency of ACTH. Expression of the HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread. The protein has a paired-like domain, and it competes with the product of PROP1 for DNA-binding. Homozygosity for inactivating mutations of HESX1 produces a complex phenotype that resembles septo-optic dysplasia. Much more needs to be learned about the role of HESX1 mutations in other forms of hypopituitarism.

Topics: Basic Helix-Loop-Helix Transcription Factors; Carrier Proteins; Homeodomain Proteins; Humans; Hypopituitarism; Membrane Proteins; Mutation; Phospholipid Transfer Proteins; Pituitary Gland; Transcription Factor HES-1; Transcription Factors

HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of septooptic dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Line; Gene Expression; Homeodomain Proteins; Humans; Hypopituitarism; Phenotype; Point Mutation; Septo-Optic Dysplasia; Transcription Factor HES-1; Transcription, Genetic

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.

Topics: Adolescent; Adult; Basic Helix-Loop-Helix Transcription Factors; Child, Preschool; Co-Repressor Proteins; DNA; DNA-Binding Proteins; Homeodomain Proteins; Human Growth Hormone; Humans; Hypopituitarism; Mutation; Nuclear Proteins; Pituitary Hormones; Repressor Proteins; Transcription Factor HES-1