Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81CG/p.Y27X)

Tod Fullston, Louise Brueton, Tracey Willis, Sunny Philip, Lesley MacPherson, Merran Finnis, Jozef Gecz, Jenny Morton

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81CG (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41-C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81CG mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.

Original languageEnglish
Pages (from-to)157-162
Number of pages6
JournalEuropean Journal of Human Genetics
Volume18
Issue number2
DOIs
Publication statusPublished - 1 Feb 2010
Externally publishedYes

Keywords

  • ARX gene
  • Burst suppression
  • Ohtahara syndrome
  • West syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Fullston, T., Brueton, L., Willis, T., Philip, S., MacPherson, L., Finnis, M., ... Morton, J. (2010). Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81CG/p.Y27X). European Journal of Human Genetics, 18(2), 157-162. https://doi.org/10.1038/ejhg.2009.139