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From Sunnybrook Health Sciences Centre (L.Z., J.B.), Toronto; Department of Medicine (H.N.L., C.S., Y.W., D.M., J.R., E.R.), Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada; Department of Genetics (A.F.M., K.L.M.), University of North Carolina at Chapel Hill; and University of Birmingham (K.E.M.), Department of Clinical Neurosciences, Institute of Biomedical Research, Queen Elizabeth Hospital, NHS Foundation Trust, Birmingham, UK.
Address correspondence and reprint requests to Dr. Ekaterina Rogaeva, Centre for Neurodegenerative Diseases, Department of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario, Canada, M5S 3H2 ekaterina.rogaeva{at}utoronto.ca
Background: About 20% of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in SOD1 and is typically transmitted as an autosomal dominant trait. However, due to reduced mutation penetrance, the disease may present in a recessive or sporadic manner.
Objective: To determine the factors responsible for the low penetrance of the SOD1 mutation.
Methods: Twelve members of a Canadian ALS family of Filipino origin were recruited for the study. SOD1 was sequenced in the proband. SOD1 expression was assessed by real-time-PCR and immunoblotting.
Results: The proband was a homozygous carrier of a novel 6 bp deletion in exon 2 (
G27/P28), the pathologic significance of which was confirmed by immunohistochemistry. Eight living family members are heterozygotes and remain unaffected at ages ranging between 48 and 85 years. Haplotype analysis showed that the deletion is a single founder mutation likely common in the Cagayan province (Philippines). The low penetrance of the mutation is explained by the fact that it enhances the naturally occurring alternative splicing of exon 2 of the SOD1 mRNA, leading to reduced transcription of the mutant allele. Indeed, Western blot analysis demonstrated the low level of SOD1 protein in carriers of the G27/P28 compared to wild-type individuals or a carrier of the A4V SOD1 mutation.
Conclusion: The enhanced splicing of exon 2 acts as a natural knock-down of the mutant SOD1 allele in the Filipino amyotrophic lateral sclerosis (ALS) family. There is a need for careful investigation of splicing isoforms of SOD1 and other ALS genes as factors influencing the severity of disease.
Abbreviations: AD = Alzheimer disease; ALS = amyotrophic lateral sclerosis; CBD = corticobasal syndrome; HCI = hyaline conglomerate inclusions; RT-PCR = reverse transcriptase–polymerase chain reaction; sALS = sporadic amyotrophic lateral sclerosis; SEDI = SOD1-exposed-dimer-interface antibody.
Supplemental data at www.neurology.org
*These authors contributed equally.
Supported by grants from the Krembil Scientific Development Seed Fund (E.R., J.R., L.Z.), Japan-Canada, the Temerty Family Foundation (L.Z.), and Canadian Institutes of Health Research (CIHR) Joint Health Research Program (E.R.); J.R. holds a Canada Research Chair and is funded by grants from the American ALS Association, US Muscular Dystrophy Association, the ALS Society of Canada, and the CIHR.
Disclosure: The authors report no disclosures.
Received July 31, 2008. Accepted in final form December 16, 2008.
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