A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult.
Human Molecular Genetics. 2012-09-21; 21(26): 5472-5483
DOI: 10.1093/hmg/dds392
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1. Hum Mol Genet. 2012 Dec 15;21(26):5472-83. doi: 10.1093/hmg/dds392. Epub 2012 Sep
21.
A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity
and increased susceptibility to proteostatic insult.
Hekman KE(1), Yu GY, Brown CD, Zhu H, Du X, Gervin K, Undlien DE, Peterson A,
Stevanin G, Clark HB, Pulst SM, Bird TD, White KP, Gomez CM.
Author information:
(1)Department of Neurology, Institute for Genomics and Systems Biology,
University of Chicago, Chicago, IL 60637, USA.
The autosomal dominant spinocerebellar ataxias (SCAs) are a genetically
heterogeneous group of disorders exhibiting cerebellar atrophy and Purkinje cell
degeneration whose subtypes arise from 31 distinct genetic loci. Our group
previously published the locus for SCA26 on chromosome 19p13.3. In this study, we
performed targeted deep sequencing of the critical interval in order to identify
candidate causative variants in individuals from the SCA26 family. We identified
a single variant that co-segregates with the disease phenotype that produces a
single amino acid substitution in eukaryotic elongation factor 2. This
substitution, P596H, sits in a domain critical for maintaining reading frame
during translation. The yeast equivalent, P580H EF2, demonstrated impaired
translocation, detected as an increased rate of -1 programmed ribosomal
frameshift read-through in a dual-luciferase assay for observing translational
recoding. This substitution also results in a greater susceptibility to
proteostatic disruption, as evidenced by a more robust activation of a reporter
gene driven by unfolded protein response activation upon challenge with
dithiothreitol or heat shock in our yeast model system. Our results present a
compelling candidate mutation and mechanism for the pathogenesis of SCA26 and
further support the role of proteostatic disruption in neurodegenerative
diseases.
DOI: 10.1093/hmg/dds392
PMCID: PMC3516132
PMID: 23001565 [Indexed for MEDLINE]