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A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 ( CRMP4 ) Gene is Associated with ALS
Author(s) -
Blasco Hélène,
BernardMarissal Nathalie,
Vourc'h Patrick,
Guettard Yves Olivier,
Sunyach Claire,
Augereau Olivier,
Khederchah Joelle,
Mouzat Kevin,
Antar Catherine,
Gordon Paul H.,
VeyratDurebex Charlotte,
Besson Gérard,
Andersen Peter M.,
Salachas François,
Meininger Vincent,
Camu William,
Pettmann Brigitte,
Andres Christian R.,
Corcia Philippe
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22329
Subject(s) - biology , excitotoxicity , neurodegeneration , missense mutation , motor neuron , axon , genetics , population , neuroscience , mutation , programmed cell death , gene , medicine , apoptosis , disease , environmental health , spinal cord
The dihydropyrimidinase‐like 3 ( DPYSL 3) or C ollapsin R esponse M ediator P rotein 4a ( CRMP 4a) 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 CRMP 4 as a risk factor for ALS . We analyzed the DPYSL 3 / CRMP 4 gene in F rench 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 F rench ALS patients (odds ratio = 2.99) but the association was not confirmed in the S wedish population. In vitro expression of mutated DPYSL 3 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 F rench 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 CRMP 4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.