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.
View: Text | PDF
Article Aging

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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Schematic of the HESX1 gene, HESX1(I26T) mutation, and Bsu36I restrictio...
Schematic of the HESX1 gene, HESX1(I26T) mutation, and Bsu36I restriction digest assay within a normal Brazilian population. (a) Genomic and protein structure of HESX1. HESX1 consists of four exons encoding a 185-AA protein. The engrailed homology domain (AAs 21–27) is encoded by exon 1 and the prd-like homeodomain by exons 2–4. (b) Homozygous missense mutation within exon 1 leads to the substitution of an isoleucine residue (codon 26) by threonine in the engrailed homology domain eh1. (c) Bsu36I restriction digests in pedigree 1 (F, father; P, patient) and 18 control samples. Digestion of a homozygous sample results in one band (104 + 115 bp fragment size), digestion of a heterozygous sample results in two bands (a 219-bp band from the normal allele and a band with the 104-bp and 115-bp fragments from the mutant allele), and digestion of a homozygous wild-type sample results in a single 219-bp band. The arrow indicates a normal control who is heterozygous for HESX1(I26T).