title: A rare motor neuron deleterious missense mutation in the DPYSL3 (CRMP4) gene is associated with ALS.
abstract: The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n = 468) and matched-controls (n = 394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio = 2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.
authors.affiliation: UMR INSERM U930, Université François-Rabelais de Tours, Tours, France. helene.blasco@univ-tours.fr
authors.forename: Hélène
authors.initials: H
authors.lastname: Blasco
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bernard-Marissal
authors.forename: Patrick
authors.initials: P
authors.lastname: Vourc'h
authors.forename: Yves Olivier
authors.initials: YO
authors.lastname: Guettard
authors.forename: Claire
authors.initials: C
authors.lastname: Sunyach
authors.forename: Olivier
authors.initials: O
authors.lastname: Augereau
authors.forename: Joelle
authors.initials: J
authors.lastname: Khederchah
authors.forename: Kevin
authors.initials: K
authors.lastname: Mouzat
authors.forename: Catherine
authors.initials: C
authors.lastname: Antar
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gordon
authors.forename: Charlotte
authors.initials: C
authors.lastname: Veyrat-Durebex
authors.forename: Gérard
authors.initials: G
authors.lastname: Besson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: William
authors.initials: W
authors.lastname: Camu
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pettmann
authors.forename: Christian R
authors.initials: CR
authors.lastname: Andres
authors.forename: Philippe
authors.initials: P
authors.lastname: Corcia
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D013548:Sweden / Q000453:epidemiology
chemical_list: C102926:DPYSL3 protein, human; D009124:Muscle Proteins