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Eur J Hum Genet. 2016 May;24(5):681-9. doi: 10.1038/ejhg.2015.176. Epub 2015 Aug 26.

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX.

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Department of Paediatrics, School of Peadiatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia.
Robinson Research Institute, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Nationwide Children's Hospital, Columbus, OH, USA.
Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.


Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms. We report two male patients with early-onset infantile spasms in whom a novel c.34G>T (p.(E12*)) variant was identified in the ARX gene. A similar variant c.81C>G (p.(Y27*)), has previously been described in two affected cousins with early-onset infantile spasms, leading to reinitiation of ARX mRNA translation resulting in an N-terminal truncated protein. We show that the novel c.34G>T (p.(E12*)) variant also reinitiated mRNA translation at the next AUG codon (c.121-123 (p.M41)), producing the same N-terminally truncated protein. The production of both of these truncated proteins was demonstrated to be at markedly reduced levels using in vitro cell assays. Using luciferase reporter assays, we demonstrate that transcriptional repression capacity of ARX was diminished by both the loss of the N-terminal corepressor octapeptide domain, as a consequence of truncation, and the marked reduction in mutant protein expression. Our study indicates that premature termination mutations very early in ARX lead to reinitiation of translation to produce N-terminally truncated protein at markedly reduced levels of expression. We conclude that even low levels of N-terminally truncated ARX is sufficient to improve the patient's phenotype compared with the severe phenotype of XLAG that includes malformations of the brain and genitalia normally seen in complete loss-of-function mutations in ARX.

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