Mutations in neurofilament genes are not a significant primary cause of non-SOD1

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Neurobiol Dis. 2005 Aug 2 MENTIONS CMT

Mutations in neurofilament genes are not a significant primary cause

of non-SOD1-mediated amyotrophic lateral sclerosis.

ML, Singleton AB, D, Ward CM, Evey C, Sapp PA, Hardy

J, Brown RH Jr, Cleveland DW.

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.

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.