Carvalho, LR;
Woods, KS;
Mendonca, BB;
Marcal, N;
Zamparini, AL;
Stifani, S;
Brickman, JM;
... Dattani, MT; + view all
(2003)
A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.
Journal of Clinical Investigation
, 112
(8)
pp. 1192-1201.
10.1172/JCI18589.
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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.
| Type: | Article |
|---|---|
| Title: | A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI18589 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/8411 |
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