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

A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction
A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction
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.
0021-9738
1192-1201
Carvalho, Luciani R.
957e8e85-9171-4a46-be3c-f1a37130310b
Woods-Townsend, Kathryn
af927fa3-30b6-47d9-8b4d-4d254b3a7aab
Mendonca, Berenice B.
1a3ae74d-9ed4-4cb8-96ef-75858a26a953
Marcal, Nathalie
e2e26eb7-fbe6-4662-b580-402474d9f3e8
Zamparini, Andrea L.
337cf0b0-ea32-4505-a547-7503bcccac86
Stifani, Stefano
89f76577-a1fe-4d80-891b-6ac08a2fcc4a
Brickman, Joshua M.
954f1fe5-8b19-4176-8976-e527def192cd
Arnhold, Ivo J.P.
505f3179-a6d5-4c45-afd9-ebeecef456bc
Dattani, Mehul T.
536002c2-9284-4800-95db-65375bb0afbd
Carvalho, Luciani R.
957e8e85-9171-4a46-be3c-f1a37130310b
Woods-Townsend, Kathryn
af927fa3-30b6-47d9-8b4d-4d254b3a7aab
Mendonca, Berenice B.
1a3ae74d-9ed4-4cb8-96ef-75858a26a953
Marcal, Nathalie
e2e26eb7-fbe6-4662-b580-402474d9f3e8
Zamparini, Andrea L.
337cf0b0-ea32-4505-a547-7503bcccac86
Stifani, Stefano
89f76577-a1fe-4d80-891b-6ac08a2fcc4a
Brickman, Joshua M.
954f1fe5-8b19-4176-8976-e527def192cd
Arnhold, Ivo J.P.
505f3179-a6d5-4c45-afd9-ebeecef456bc
Dattani, Mehul T.
536002c2-9284-4800-95db-65375bb0afbd

Carvalho, Luciani R., Woods-Townsend, Kathryn, Mendonca, Berenice B., Marcal, Nathalie, Zamparini, Andrea L., Stifani, Stefano, Brickman, Joshua M., Arnhold, Ivo J.P. and Dattani, Mehul T. (2003) A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. Journal of Clinical Investigation, 112 (8), 1192-1201. (doi:10.1172/JCI18589). (PMID:14561704)

Record type: Article

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.

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More information

Published date: 15 October 2003
Organisations: Southampton Education School, Mathematics, Science & Health Education

Identifiers

Local EPrints ID: 340435
URI: http://eprints.soton.ac.uk/id/eprint/340435
ISSN: 0021-9738
PURE UUID: 841dedca-abcf-4560-bccd-1324bf1fdc93
ORCID for Kathryn Woods-Townsend: ORCID iD orcid.org/0000-0003-3376-6988

Catalogue record

Date deposited: 26 Mar 2015 10:28
Last modified: 09 Nov 2021 03:13

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Contributors

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

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