期刊
HUMAN MOLECULAR GENETICS
卷 21, 期 26, 页码 5472-5483出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds392
关键词
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资金
- Lilly-Life Sciences Research Foundation fellowship
- Graduate Training in Growth and Development program at the University of Chicago [T32 HD009007]
- Bob Allison Ataxia Research Center
- National Ataxia Foundation
- Verum Foundation
- 'Association Connaitre les Syndromes Cerebelleux' (France)
- European Union (6th PCRD call: EUROSCA)
- CTSA [UL1 TR000430]
- NIH [R03-NS52582]
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.
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