title: A mechanism for low penetrance in an ALS family with a novel SOD1 deletion.
abstract: 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 (DeltaG27/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 DeltaG27/P28 compared to wild-type individuals or a carrier of the A4V SOD1 mutation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Neurodegenerative Diseases, Department of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario, Canada, M5S 3H2.
authors.forename: L
authors.initials: L
authors.lastname: Zinman
authors.forename: H N
authors.initials: HN
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Wakutani
authors.forename: A F
authors.initials: AF
authors.lastname: Marvelle
authors.forename: D
authors.initials: D
authors.lastname: Moreno
authors.forename: K E
authors.initials: KE
authors.lastname: Morrison
authors.forename: K L
authors.initials: KL
authors.lastname: Mohlke
authors.forename: J
authors.initials: J
authors.lastname: Bilbao
authors.forename: J
authors.initials: J
authors.lastname: Robertson
authors.forename: E
authors.initials: E
authors.lastname: Rogaeva