title: NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis.
abstract: Mutations in NIPA1 cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease characterized by an (upper) motor neuron phenotype. Deletions of NIPA1 have been associated with a higher susceptibility to amyotrophic lateral sclerosis (ALS). The exact role of genetic variation in NIPA1 in ALS susceptibility and disease course is, however, not known. We sequenced the entire coding sequence of NIPA1 and genotyped a polyalanine repeat located in the first exon of NIPA1. A total of 2292 ALS patients and 2777 controls from three independent European populations were included. We identified two sequence variants that have a potentially damaging effect on NIPA1 protein function. Both variants were identified in ALS patients; no damaging variants were found in controls. Secondly, we found a significant effect of 'long' polyalanine repeat alleles on disease susceptibility: odds ratio = 1.71, P = 1.6 × 10(-4). Our analyses also revealed a significant effect of 'long' alleles on patient survival [hazard ratio (HR) = 1.60, P = 4.2 × 10(-4)] and on the age at onset of symptoms (HR = 1.37, P = 4.6 × 10(-3)). In patients carrying 'long' alleles, median survival was 3 months shorter than patients with 'normal' genotypes and onset of symptoms occurred 3.6 years earlier. Our data show that NIPA1 polyalanine repeat expansions are a common risk factor for ALS and modulate disease course.
authors.affiliation: Department of Neurology, University Medical Center Utrecht, Heidelberglaan , Utrecht, The Netherlands
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.forename: Max
authors.initials: M
authors.lastname: Koppers
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Stefan
authors.initials: S
authors.lastname: Waibel
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Paul W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*
chemical_list: D008565:Membrane Proteins; C478824:NIPA1 protein, human; D010455:Peptides; C019529:polyalanine