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Sporadic amyotrophic lateral sclerosis (SALS) is a motor neuron degenerative disease of unknown etiology. Current thinking on SALS is that multiple genetic and environmental factors contribute to disease liability. Since neuronal acetylcholine receptors (nAChRs) are part of the glutamatergic pathway, we searched for sequence variants in  CHRNA3 ,  CHRNA4  and  CHRNB4  genes, encoding neuronal nicotinic AChR subunits, in 245 SALS patients and in 450 controls. We characterized missense variants by  in vitro  mutagenesis, cell transfection and electrophysiology. Sequencing the regions encoding the intracellular loop of AChRs subunits disclosed 15 missense variants (6.1%) in 14 patients compared with only six variants (1.3%) in controls ( P  = 0.001; OR 4.48, 95% CI 1.7–11.8). The frequency of variants in exons encoding extracellular and transmembrane domains and in intronic regions did not differ. NAChRs formed by mutant α3 and α4 and wild-type (WT) β4 subunits exhibited altered affinity for nicotine (Nic), reduced use-dependent rundown of Nic-activated currents (I Nic ) and reduced desensitization leading to sustained intracellular Ca 2+  concentration, in comparison with WT-nAChR. The cellular loop has a crucial importance for receptor trafficking and regulating ion channel properties. Missense variants in this domain are significantly over-represented in SALS patients and alter functional properties of nAChR  in vitro , resulting in increased Ca 2+  entry into the cells. We suggest that these  gain-of-function  variants might contribute to disease liability in a subset of SALS because Ca 2+  signals mediate nAChR's neuromodulatory effects, including regulation of glutamate release and control of cell survival.

human molecular genetics

Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis