Abstract
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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Acknowledgements
We thank the patients, their families and physicians for their participation in this study. We also thank Nancy Briggs from the Robinson Research Institute, University of Adelaide for the statistical analysis. The Neurogenetics research program in the Department of Paediatrics, University of Adelaide, Australia was funded by the Australian National Health and Medical Research Council (Grant No. 1063025). CS is supported Australian Research Council (Future Fellowship FT120100086).
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Moey, C., Topper, S., Karn, M. et al. Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX. Eur J Hum Genet 24, 681–689 (2016). https://doi.org/10.1038/ejhg.2015.176
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DOI: https://doi.org/10.1038/ejhg.2015.176
