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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

34 Citazioni (Scopus)

Abstract

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 alpha3 and alpha4 and wild-type (WT) beta4 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.
Lingua originaleEnglish
pagine (da-a)3997-4006
Numero di pagine10
RivistaHUMAN MOLECULAR GENETICS
Stato di pubblicazionePubblicato - 2009

Keywords

  • ALS
  • nAChR

Fingerprint Entra nei temi di ricerca di 'Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis.'. Insieme formano una fingerprint unica.

Cita questo