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.

The rs696880 Polymorphism in the Nogo-A Receptor Gene (RTN4R) Is Associated With Susceptibility to Sporadic Amyotrophic Lateral Sclerosis in the Chinese Population

“…Only the rs1567871 SNP was included in both studies. In Amy et al’s ( 2015 ) study, the rs1567871 C allele was associated with SALS in the French population. However, the rs1567871 C allele was not a risk allele for SALS in the Chinese population.…”

“…Four SNPs, rs854971, rs887765, rs696880 and rs1567871, were included in our study. Three SNPs, rs701427, rs701421 and rs1567871, were included in the French study (Amy et al, 2015 ). The MAFs of rs701427 and rs701421 were both lower than 0.2% in the Han Chinese population; therefore, these two SNPs were not included in our study.…”

“…Recently, two non-coding variants (rs701427 A and rs1567871 C) in the Nogo-A receptor gene ( RTN4R ) were reported to confer susceptibility to SALS in the French population (Amy et al, 2015 ). Moreover, rs701427 showed a significant correlation with reduced gene expression.…”

Genetic Variants Were Associated With the Prognosis of Head and Neck Squamous Carcinoma

“…The risk allele C of rs854936 significantly raised the expression of RTN4R and high expression of RTN4R decreased the rate of HNC survival. RTN4R (reticulon 4 receptor), which is an essential role in axonal regeneration and structural plasticity in the central nervous system (19,20), has been elucidated to be associated with the risk for sporadic amyotrophic lateral sclerosis (21,22) and schizophrenia (23,24). That findings indicated that RTN4R might be a new risk factor for predicting cancer prognosis.…”

Spatiotemporal and Long Lasting Modulation of 11 Key Nogo Signaling Genes in Response to Strong Neuroexcitation

“…Increased levels of Nogo-A have been reported in schizophrenia (Novak et al, 2002), multiple sclerosis (Satoh et al, 2005), temporal lobe epilepsy (Bandtlow et al, 2004) and Alzheimer’s disease (Gil et al, 2006). An increasing number of mutations and genetic variants in genes depicted in Figure 1 have been found coupled to neuropsychiatric and neurodegenerative disorders, including schizophrenia (NgR1/Nogo-A: Budel et al, 2008; Willi and Schwab, 2013; Andrews and Fernandez-Enright, 2015), (LGI1/NgR1: Thomas et al, 2016), ALS (NgR1: Amy et al, 2015), Pelizaeus-Merzbacher disease (MAG: Lossos et al, 2015), Parkinson’s disease (Lingo-1: Chen et al, 2015), Tourette syndrome/OCD/ADHD (Olfactomedin: Bertelsen et al, 2015) and epilepsy (LgI1: Fukata et al, 2010); (ADAM22: Muona et al, 2016), further emphasizing the importance of normal Nogo-type control of synaptic plasticity. Current knowledge has also led to the initiations of clinical trials in spinal cord injury (NCT00406016), multiple sclerosis (Ineichen et al, 2017), and ALS in which disease a large phase II trial shows no positive effects of Nogo-A antibodies (Meininger et al, 2014).…”