A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis.
Peripherin is a neuronal intermediate filament associated with inclusion bodies in motor neurons of patients with amyotrophic lateral sclerosis (ALS). A possible peripherin involvement in ALS pathogenesis has been suggested based on studies with transgenic mouse overexpressors and with a toxic splicing variant of the mouse peripherin gene. However, the existence of peripherin gene mutations in human ALS has not yet been documented. Therefore, we screened for sequence variants of the peripherin gene (PRPH) in a cohort of ALS patients including familial and sporadic cases. We identified 18 polymorphic variants of PRPH detected in both ALS and age-matched control populations. Two additional PRPH variants were discovered in ALS cases but not in 380 control individuals. One variant consisted of a nucleotide insertion in intron 8 (PRPH(IVS8)(-36insA)), whereas the other one consisted of a 1-bp deletion within exon 1 (PRPH(228delC)), predicting a truncated peripherin species of 85 amino acids. Remarkably, expression of this frameshift peripherin mutant in SW13 cells resulted in disruption of neurofilament network assembly. These results suggest that PRPH mutations may be responsible for a small percentage of ALS, cases and they provide further support of the view that neurofilament disorganization may contribute to pathogenesis.
Gros-Louis
François
F
Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital Research Institute, Montreal, Québec H3G 1A4, Canada.
Larivière
Roxanne
R
Gowing
Geneviève
G
Laurent
Sandra
S
Camu
William
W
Bouchard
Jean-Pierre
JP
Meininger
Vincent
V
Rouleau
Guy A
GA
Julien
Jean-Pierre
JP
D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics*; D001483:Base Sequence; D016368:Frameshift Mutation; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016900:Neurofilament Proteins / Q000737:chemistry; D064531:Peripherins
D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C578994:PRPH protein, human; D064531:Peripherins; C579005:Prph protein, mouse; C044882:neurofilament protein L; C061195:neurofilament protein M