Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/100023
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Type: Journal article
Title: Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX
Author: Moey, C.
Topper, S.
Karn, M.
Johnson, A.
Das, S.
Vidaurre, J.
Shoubridge, C.
Citation: European Journal of Human Genetics, 2016; 24(5):681-689
Publisher: Nature Publishing Group
Issue Date: 2016
ISSN: 1018-4813
1476-5438
Statement of
Responsibility: 
Ching Moey, Scott Topper, Mary Karn, Amy Knight Johnson, Soma Das, Jorge Vidaurre and Cheryl Shoubridge
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.
Keywords: Humans
Spasms, Infantile
Genetic Diseases, X-Linked
Homeodomain Proteins
Transcription Factors
RNA, Messenger
Codon, Initiator
Siblings
Peptide Chain Initiation, Translational
Mutation
Infant
Male
HEK293 Cells
Rights: © 2016 Macmillan Publishers Limited All rights reserved 1018-4813/16
DOI: 10.1038/ejhg.2015.176
Grant ID: http://purl.org/au-research/grants/nhmrc/1063025
http://purl.org/au-research/grants/arc/FT120100086
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