A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS

Hélène Blasco, Nathalie Bernard-Marissal, Patrick Vourc'h, Yves Olivier Guettard, Claire Sunyach, Olivier Augereau, Joelle Khederchah, Kevin Mouzat, Catherine Antar, Paul H. Gordon, Charlotte Veyrat-Durebex, Gérard Besson, Peter M. Andersen, F. Salachas, V. Meininger, William Camu, Brigitte Pettmann, Christian R. Andres, P. Corcia, V. Pautot & 38 others G. Nicolas, L. Rumbach, P. Clavelou, N. Guy, G. Besson, A. Destée, V. Brunaud-Danel, P. Couratier, B. Funalot, E. Broussole, C. Vial, N. Vandenberghe, W. Camu, R. Morales, N. Pageot, M. Debouverie, S. Pittion, C. Desnuelle, M. H. Soriani, G. Lemasson, V. Meininger, F. Salachas, P. F. Pradat, M. Dib, G. Bruneteau, N. Leforestier, J. Pouget, A. Verschuren, F. Viader, L. Carluer, C. Tranchant, M. C. Fleury, J. C. Antoine, J. P. Camdessanche, M. C. Arne-Bes, P. Cintas, P. Corcia, J. Praline

Research output: Contribution to journalArticle

12 Citations (Scopus)

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. Twenty-four hours after electroporation, motor neuron survival was decreased to 58 ± 4% (P < 0.001) of expected when expressing mCRMP4 compared with wtCRMP4 or EGFP. Axonal growth, evaluated at 20 hr, was also reduced by 62 ± 10% (P < 0.001) in motor neurons expressing the mutated form of CRMP4 compared with EGFP expressing cells, whereas expression of the wildtype form of CRMP4 did not significantly affect axonal growth (87 ± 7%)

LanguageEnglish
Pages953-960
Number of pages8
JournalHuman Mutation
Volume34
Issue number7
DOIs
Publication statusPublished - 1 Jul 2013

Fingerprint

dihydropyrimidinase
Motor Neurons
Missense Mutation
Growth
Genes
Semaphorin-3A
Population
Axonal Transport
Electroporation
Axons
Glutamic Acid
Proteins
Oxidative Stress
Cell Death
Cell Culture Techniques
Odds Ratio
Survival

Keywords

  • ALS
  • CRMP4
  • DPYSL3
  • Risk factor

Cite this

Blasco, H., Bernard-Marissal, N., Vourc'h, P., Guettard, Y. O., Sunyach, C., Augereau, O., ... Praline, J. (2013). A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS. Human Mutation, 34(7), 953-960. https://doi.org/10.1002/humu.22329
Blasco, Hélène ; Bernard-Marissal, Nathalie ; Vourc'h, Patrick ; Guettard, Yves Olivier ; Sunyach, Claire ; Augereau, Olivier ; Khederchah, Joelle ; Mouzat, Kevin ; Antar, Catherine ; Gordon, Paul H. ; Veyrat-Durebex, Charlotte ; Besson, Gérard ; Andersen, Peter M. ; Salachas, F. ; Meininger, V. ; Camu, William ; Pettmann, Brigitte ; Andres, Christian R. ; Corcia, P. ; Pautot, V. ; Nicolas, G. ; Rumbach, L. ; Clavelou, P. ; Guy, N. ; Besson, G. ; Destée, A. ; Brunaud-Danel, V. ; Couratier, P. ; Funalot, B. ; Broussole, E. ; Vial, C. ; Vandenberghe, N. ; Camu, W. ; Morales, R. ; Pageot, N. ; Debouverie, M. ; Pittion, S. ; Desnuelle, C. ; Soriani, M. H. ; Lemasson, G. ; Meininger, V. ; Salachas, F. ; Pradat, P. F. ; Dib, M. ; Bruneteau, G. ; Leforestier, N. ; Pouget, J. ; Verschuren, A. ; Viader, F. ; Carluer, L. ; Tranchant, C. ; Fleury, M. C. ; Antoine, J. C. ; Camdessanche, J. P. ; Arne-Bes, M. C. ; Cintas, P. ; Corcia, P. ; Praline, J. / A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS. In: Human Mutation. 2013 ; Vol. 34, No. 7. pp. 953-960.
@article{0dbb682f823e442e95ed00a99e6f4d51,
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. Twenty-four hours after electroporation, motor neuron survival was decreased to 58 ± 4{\%} (P < 0.001) of expected when expressing mCRMP4 compared with wtCRMP4 or EGFP. Axonal growth, evaluated at 20 hr, was also reduced by 62 ± 10{\%} (P < 0.001) in motor neurons expressing the mutated form of CRMP4 compared with EGFP expressing cells, whereas expression of the wildtype form of CRMP4 did not significantly affect axonal growth (87 ± 7{\%})",
keywords = "ALS, CRMP4, DPYSL3, Risk factor",
author = "H{\'e}l{\`e}ne Blasco and Nathalie Bernard-Marissal and Patrick Vourc'h and Guettard, {Yves Olivier} and Claire Sunyach and Olivier Augereau and Joelle Khederchah and Kevin Mouzat and Catherine Antar and Gordon, {Paul H.} and Charlotte Veyrat-Durebex and G{\'e}rard Besson and Andersen, {Peter M.} and F. Salachas and V. Meininger and William Camu and Brigitte Pettmann and Andres, {Christian R.} and P. Corcia and V. Pautot and G. Nicolas and L. Rumbach and P. Clavelou and N. Guy and G. Besson and A. Dest{\'e}e and V. Brunaud-Danel and P. Couratier and B. Funalot and E. Broussole and C. Vial and N. Vandenberghe and W. Camu and R. Morales and N. Pageot and M. Debouverie and S. Pittion and C. Desnuelle and Soriani, {M. H.} and G. Lemasson and V. Meininger and F. Salachas and Pradat, {P. F.} and M. Dib and G. Bruneteau and N. Leforestier and J. Pouget and A. Verschuren and F. Viader and L. Carluer and C. Tranchant and Fleury, {M. C.} and Antoine, {J. C.} and Camdessanche, {J. P.} and Arne-Bes, {M. C.} and P. Cintas and P. Corcia and J. Praline",
year = "2013",
month = "7",
day = "1",
doi = "10.1002/humu.22329",
language = "English",
volume = "34",
pages = "953--960",
journal = "Human Mutation",
issn = "1059-7794",
number = "7",

}

Blasco, H, Bernard-Marissal, N, Vourc'h, P, Guettard, YO, Sunyach, C, Augereau, O, Khederchah, J, Mouzat, K, Antar, C, Gordon, PH, Veyrat-Durebex, C, Besson, G, Andersen, PM, Salachas, F, Meininger, V, Camu, W, Pettmann, B, Andres, CR, Corcia, P, Pautot, V, Nicolas, G, Rumbach, L, Clavelou, P, Guy, N, Besson, G, Destée, A, Brunaud-Danel, V, Couratier, P, Funalot, B, Broussole, E, Vial, C, Vandenberghe, N, Camu, W, Morales, R, Pageot, N, Debouverie, M, Pittion, S, Desnuelle, C, Soriani, MH, Lemasson, G, Meininger, V, Salachas, F, Pradat, PF, Dib, M, Bruneteau, G, Leforestier, N, Pouget, J, Verschuren, A, Viader, F, Carluer, L, Tranchant, C, Fleury, MC, Antoine, JC, Camdessanche, JP, Arne-Bes, MC, Cintas, P, Corcia, P & Praline, J 2013, 'A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS', Human Mutation, vol. 34, no. 7, pp. 953-960. https://doi.org/10.1002/humu.22329

A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS. / Blasco, Hélène; Bernard-Marissal, Nathalie; Vourc'h, Patrick; Guettard, Yves Olivier; Sunyach, Claire; Augereau, Olivier; Khederchah, Joelle; Mouzat, Kevin; Antar, Catherine; Gordon, Paul H.; Veyrat-Durebex, Charlotte; Besson, Gérard; Andersen, Peter M.; Salachas, F.; Meininger, V.; Camu, William; Pettmann, Brigitte; Andres, Christian R.; Corcia, P.; Pautot, V.; Nicolas, G.; Rumbach, L.; Clavelou, P.; Guy, N.; Besson, G.; Destée, A.; Brunaud-Danel, V.; Couratier, P.; Funalot, B.; Broussole, E.; Vial, C.; Vandenberghe, N.; Camu, W.; Morales, R.; Pageot, N.; Debouverie, M.; Pittion, S.; Desnuelle, C.; Soriani, M. H.; Lemasson, G.; Meininger, V.; Salachas, F.; Pradat, P. F.; Dib, M.; Bruneteau, G.; Leforestier, N.; Pouget, J.; Verschuren, A.; Viader, F.; Carluer, L.; Tranchant, C.; Fleury, M. C.; Antoine, J. C.; Camdessanche, J. P.; Arne-Bes, M. C.; Cintas, P.; Corcia, P.; Praline, J.

In: Human Mutation, Vol. 34, No. 7, 01.07.2013, p. 953-960.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS

AU - Blasco, Hélène

AU - Bernard-Marissal, Nathalie

AU - Vourc'h, Patrick

AU - Guettard, Yves Olivier

AU - Sunyach, Claire

AU - Augereau, Olivier

AU - Khederchah, Joelle

AU - Mouzat, Kevin

AU - Antar, Catherine

AU - Gordon, Paul H.

AU - Veyrat-Durebex, Charlotte

AU - Besson, Gérard

AU - Andersen, Peter M.

AU - Salachas, F.

AU - Meininger, V.

AU - Camu, William

AU - Pettmann, Brigitte

AU - Andres, Christian R.

AU - Corcia, P.

AU - Pautot, V.

AU - Nicolas, G.

AU - Rumbach, L.

AU - Clavelou, P.

AU - Guy, N.

AU - Besson, G.

AU - Destée, A.

AU - Brunaud-Danel, V.

AU - Couratier, P.

AU - Funalot, B.

AU - Broussole, E.

AU - Vial, C.

AU - Vandenberghe, N.

AU - Camu, W.

AU - Morales, R.

AU - Pageot, N.

AU - Debouverie, M.

AU - Pittion, S.

AU - Desnuelle, C.

AU - Soriani, M. H.

AU - Lemasson, G.

AU - Meininger, V.

AU - Salachas, F.

AU - Pradat, P. F.

AU - Dib, M.

AU - Bruneteau, G.

AU - Leforestier, N.

AU - Pouget, J.

AU - Verschuren, A.

AU - Viader, F.

AU - Carluer, L.

AU - Tranchant, C.

AU - Fleury, M. C.

AU - Antoine, J. C.

AU - Camdessanche, J. P.

AU - Arne-Bes, M. C.

AU - Cintas, P.

AU - Corcia, P.

AU - Praline, J.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - 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. Twenty-four hours after electroporation, motor neuron survival was decreased to 58 ± 4% (P < 0.001) of expected when expressing mCRMP4 compared with wtCRMP4 or EGFP. Axonal growth, evaluated at 20 hr, was also reduced by 62 ± 10% (P < 0.001) in motor neurons expressing the mutated form of CRMP4 compared with EGFP expressing cells, whereas expression of the wildtype form of CRMP4 did not significantly affect axonal growth (87 ± 7%)

AB - 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. Twenty-four hours after electroporation, motor neuron survival was decreased to 58 ± 4% (P < 0.001) of expected when expressing mCRMP4 compared with wtCRMP4 or EGFP. Axonal growth, evaluated at 20 hr, was also reduced by 62 ± 10% (P < 0.001) in motor neurons expressing the mutated form of CRMP4 compared with EGFP expressing cells, whereas expression of the wildtype form of CRMP4 did not significantly affect axonal growth (87 ± 7%)

KW - ALS

KW - CRMP4

KW - DPYSL3

KW - Risk factor

UR - http://www.scopus.com/inward/record.url?scp=84879422064&partnerID=8YFLogxK

U2 - 10.1002/humu.22329

DO - 10.1002/humu.22329

M3 - Article

VL - 34

SP - 953

EP - 960

JO - Human Mutation

T2 - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 7

ER -

Blasco H, Bernard-Marissal N, Vourc'h P, Guettard YO, Sunyach C, Augereau O et al. A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS. Human Mutation. 2013 Jul 1;34(7):953-960. https://doi.org/10.1002/humu.22329