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

Hum Mol Genet 2009 Oct 23;18(20):3997-4006. Epub 2009 Jul 23.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Roma, Italy.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddp339DOI Listing
October 2009
25 Reads

Publication Analysis

Top Keywords

missense variants
16
amyotrophic lateral
8
neuronal nicotinic
8
sporadic amyotrophic
8
lateral sclerosis
8
disease liability
8
contribute disease
8
variants
8
sals patients
8
sals
5
alpha3 alpha4
4
mutant alpha3
4
alpha4 wild-type
4
wild-type beta4
4
beta4 subunits
4
formed mutant
4
nachrs formed
4
domains intronic
4
intronic regions
4
regions differ
4

References

(Supplied by CrossRef)

Rowland et al.
New England Journal of Medicine 2001

Greenway et al.
Nature genetics 2006

Science 2008

Vance et al.
Science 2009

Kwiatkowski et al.
Science 2009

Simpson et al.
Biochimica et Biophysica Acta. Protein Structure and Molecular Enzymology 2006

Graham et al.
Journal of Neurology, Neurosurgery & Psychiatry 1997

Schymick et al.
Lancet. Neurology 2007

New England Journal of Medicine 2007

Rademakers et al.
Lancet. Neurology 2007

Human Molecular Genetics 2008

Similar Publications