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

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  • Luciani R Carvalho
  • Kathryn S Woods
  • Berenice B Mendonca
  • Nathalie Marcal
  • Andrea L Zamparini
  • Stefano Stifani
  • Brickman, Joshua Mark
  • Ivo J P Arnhold
  • Mehul T Dattani

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.

OriginalsprogEngelsk
TidsskriftThe Journal of Clinical Investigation
Vol/bind112
Udgave nummer8
Sider (fra-til)1192-201
Antal sider10
ISSN0021-9738
DOI
StatusUdgivet - okt. 2003

ID: 129061792