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.
Bibliographical noteFunding Information:
C.D.B. was supported by a Lilly-Life Sciences Research Foundation fellowship. K.E.H. was supported by the Graduate Training in Growth and Development program at the University of Chicago (T32 HD009007). G.-Y.Y. was supported by the Bob Allison Ataxia Research Center and the National Ataxia Foundation. This work was supported financially by the Verum Foundation, the ‘Association Connaitre les Syndromes Cérébelleux’ (France) and the European Union (6th PCRD call: EUROSCA), CTSA UL1 TR000430, and by NIH (R03-NS52582).