title: Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis.
abstract: While 1 to 2% of amyotrophic lateral sclerosis (ALS) is caused by mutations in the SOD1 gene, the basis of the remaining instances of inherited disease is unknown. Neuropathology, mouse modeling, and human genetics have implicated neurofilaments in the pathogenesis of motor neuron diseases such as ALS and Charcot-Marie-Tooth disease (CMT). A systematic analysis of the coding region and intron-exon boundaries of all three neurofilament genes is now reported from DNA samples derived from more than 200 non-SOD1 linked familial and sporadic ALS patients, along with >400 non-disease control individuals. Rare variants within each of the three neurofilament subunits that are predicted to affect neurofilament assembly properties were identified at higher frequency in non-SOD1 mutant ALS samples. However, none could be unambiguously linked to dominantly inherited disease. Thus, mutations in neurofilaments are possible risk factors that may contribute to pathogenesis in ALS in conjunction with one or more additional genetic or environmental factors, but are not significant primary causes of ALS.
authors.affiliation: Ludwig Institute for Cancer Research and Department of Neurosciences, University of California at San Diego, 9500 Gilman Drive, CMM-E/Room 3072, La Jolla, CA 92093-0670, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Garcia
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ward
authors.forename: Crystal
authors.initials: C
authors.lastname: Evey
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sapp
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D007438:Introns / Q000235:genetics; D016900:Neurofilament Proteins / Q000235:genetics*; D017354:Point Mutation; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D016900:Neurofilament Proteins; C000606290:SOD1 protein, human; C044882:neurofilament protein L; C051774:neurofilament protein H; C061195:neurofilament protein M; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1