NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis
| Autor: | Thomas Gasser, Philip Van Damme, Max Koppers, R. Jeroen Pasterkamp, Wim Robberecht, Robin Lemmens, Albert C. Ludolph, Hylke M. Blauw, Thomas F. Meyer, Leonard H. van den Berg, Claudia Schulte, Wouter van Rheenen, Jan H. Veldink, Edwin Cuppen, Paul W.J. van Vught, Stefan Waibel |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2012 |
| Předmět: |
Genotype
Hereditary spastic paraplegia chemistry [Peptides] Biology Degenerative disease ddc:570 Genetic variation Genetics medicine Humans Allele Amyotrophic lateral sclerosis Molecular Biology Genetics (clinical) NIPA1 protein human Alleles metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis polyalanine Genetic Variation Membrane Proteins General Medicine Odds ratio medicine.disease genetics [Amyotrophic Lateral Sclerosis] genetics [Membrane Proteins] Age of onset Peptides metabolism [Membrane Proteins] |
| Zdroj: | Human molecular genetics 21(11), 2497-2502 (2012). doi:10.1093/hmg/dds064 Human Molecular Genetics, 21(11), 2497-2502. Oxford University Press |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/dds064 |
| Popis: | 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 x 10(-4). Our analyses also revealed a significant effect of 'long' alleles on patient survival [hazard ratio (HR) = 1.60, P = 4.2 x 10(-4)] and on the age at onset of symptoms (HR = 1.37, P = 4.6 x 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. |
| Databáze: | OpenAIRE |
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