Journal Article

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

Mario Sabatelli, Fabrizio Eusebi, Ammar Al-Chalabi, Amelia Conte, Francesca Madia, Marco Luigetti, Irene Mancuso, Cristina Limatola, Flavia Trettel, Fabrizia Sobrero, Silvia Di Angelantonio, Francesca Grassi, Amalia Di Castro, Claudia Moriconi, Sergio Fucile, Serena Lattante, Giuseppe Marangi, Marina Murdolo, Daniela Orteschi, Alessandra Del Grande, Pietro Tonali, Giovanni Neri and Marcella Zollino

in Human Molecular Genetics

Volume 18, issue 20, pages 3997-4006
Published in print October 2009 | ISSN: 0964-6906
Published online July 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp339
Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis

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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 (INic) and reduced desensitization leading to sustained intracellular Ca2+ 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 Ca2+ entry into the cells. We suggest that these gain-of-function variants might contribute to disease liability in a subset of SALS because Ca2+ signals mediate nAChR's neuromodulatory effects, including regulation of glutamate release and control of cell survival.

Journal Article.  5559 words.  Illustrated.

Subjects: Genetics and Genomics

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