A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

J Clin Invest. 2003 Oct;112(8):1192-201. doi: 10.1172/JCI18589.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Basic Helix-Loop-Helix Transcription Factors
  • Child, Preschool
  • DNA / metabolism
  • DNA-Binding Proteins / physiology*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / physiology
  • Human Growth Hormone / deficiency
  • Humans
  • Hypopituitarism / etiology
  • Hypopituitarism / genetics*
  • Mutation*
  • Nuclear Proteins / physiology*
  • Pituitary Hormones / deficiency
  • Repressor Proteins / physiology*
  • Transcription Factor HES-1


  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • HESX1 protein, human
  • Hes1 protein, mouse
  • Hesx1 protein, mouse
  • Homeodomain Proteins
  • Nuclear Proteins
  • Pituitary Hormones
  • Repressor Proteins
  • TLE1 protein, human
  • Transcription Factor HES-1
  • gro protein, Drosophila
  • Human Growth Hormone
  • HES1 protein, human
  • DNA