A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction
Luciani R. Carvalho, … , Ivo J.P. Arnhold, Mehul T. Dattani
Luciani R. Carvalho, … , Ivo J.P. Arnhold, Mehul T. Dattani
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1192-1201. https://doi.org/10.1172/JCI18589.
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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

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

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Figure 7

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Interaction of HESX1 with Gro/TLE. HEK 293 cells were transfected with p...
Interaction of HESX1 with Gro/TLE. HEK 293 cells were transfected with plasmids encoding FLAG epitope–tagged HESX1 (lanes 1 and 4), HESX1(I26T) (lanes 2 and 5), or a truncated form of the bHLH protein Hes1, lacking the C-terminal WRPW motif (lanes 3 and 6). (b and d) Cell lysates were prepared and subjected to immunoprecipitation with anti–FLAG epitope antibodies, followed by SDS-PAGE. (a and c) One-eighth of each input lysate, collected prior to incubation with antibodies, was also subjected to gel electrophoresis. After transfer to nitrocellulose, Western blotting (WB) was performed with either anti-FLAG (a and b) or anti–Gro/TLE (pan-TLE; c and d) antibodies. Both HESX1 and HESX1(I26T) migrated as roughly 32-kDa proteins, but only HESX1 coimmunoprecipitated with endogenous Gro/TLE proteins of roughly 95 kDa. The specificity of this interaction was demonstrated further by the finding that Hes1ΔWRPW also failed to interact with Gro/TLE, as previously shown (22). Positions of migration of the IgG heavy chain (HC) and light chain (LC) are indicated. Positions of size standards are indicated in kilodaltons.