A common functional allele of the Nogo receptor gene, reticulon 4 receptor (RTN4R), is associated with sporadic amyotrophic lateral sclerosis in a French population

Abstract

Amyotrophic lateral sclerosis is sporadic (SALS) in 90% of cases and has complex environmental and genetic influences. Nogo protein inhibits neurite outgrowth and is overexpressed in muscle in ALS. Our aims were to study the reticulon 4 receptor gene RTN4R which encodes Nogo 1 receptor (NgR1) in SALS, to test if the variants were associated with variable expression of the gene and whether NgR1 protein expression was modified in a transgenic mouse model of ALS. We genotyped three single nucleotide polymorphisms (SNPs; rs701421, rs701427, and rs1567871) of the RTN4R gene in 364 SALS French patients and 430 controls. We examined expression of RTN4R mRNA by quantitative PCR in control post mortem human brain tissue. We determined the expression of NgR1 protein in spinal motor neurons from a SOD1 G86R ALS mouse model. We observed significant associations between SALS and RTN4R alleles. Messenger RNA expression from RTN4R in human cortical brain tissue correlated significantly with the genotypes of rs701427. NgR1 protein expression was reduced in Nogo A positive motor neurons from diseased transgenic animals. In conclusion, these observations suggest that a functional RTN4R gene variant is associated with SALS. This variant may act in concert with other genetic variants or environmental influences.

Keywords::

• Nogo-66 receptor
• reticulon 4 receptor gene (RTN4R)
• sporadic amyotrophic lateral sclerosis
• association study
• SNP
• motor neurons
• gene expression

Acknowledgements

We thank the control persons and patient participants in this research. This study was supported by the Association pour la Recherche sur la Sclérose Latérale Amyotrophique (ARSLA) and by the Federal Ministry for Education and Research, Germany, as part of the ‘Med program (FKZ: 01ZX1311A, see (43)). We thank the French ALS study group for participating in the recruitment of patients and controls: V. Pautot and G. Nicolas (Angers), L. Rumbach (Besançon), P. Clavelou and N. Guy (Clermont-Ferrand), G. Besson (Grenoble), A. Destée and V. Brunaud-Danel (Lille), P. Couratier and B. Funalot (Limoges), E. Broussole, C. Vial and N. Vandenberghe (Lyon), W. Camu , R. Morales and N. Pageot (Montpellier), M. Debouverie and S. Pittion (Nancy), C. Desnuelle and M.H. Soriani (Nice), G. Lemasson (Bordeaux), V. Meininger, F. Salachas, P.-F. Pradat, M. Dib, G. Bruneteau and N. Leforestier (Paris), J. Pouget and A. Verschuren (Marseille), F. Viader and L. Carluer (Caen), C. Tranchant and M.C. Fleury (Strasbourg), J.-C. Antoine and J.P. Camdessanche (Saint-Etienne). M.-C. Arne-Bes and P. Cintas (Toulouse), P. Corcia and J. Praline (Tours).

We thank François Wurmser and Céline Brulard for help in bioinformatics.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Supplementary material available online

Supplementary Figure I and Table I.