TY - JOUR
T1 - NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis
AU - Blauw, Hylke M.
AU - Van rheenen, Wouter
AU - Koppers, Max
AU - Van Damme, Philip
AU - Waibel, Stefan
AU - Lemmens, Robin
AU - Van Vught, Paul W. J.
AU - Meyer, Thomas
AU - Schulte, Claudia
AU - Gasser, Thomas
AU - Cuppen, Edwin
AU - Pasterkamp, R. Jeroen
AU - Robberecht, Wim
AU - Ludolph, Albert C.
AU - Veldink, Jan H.
AU - Van den Berg, Leonard H.
PY - 2012/6
Y1 - 2012/6
N2 - 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. © The Author 2012. Published by Oxford University Press. All rights reserved.
AB - 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. © The Author 2012. Published by Oxford University Press. All rights reserved.
UR - http://www.scopus.com/inward/record.url?scp=84861156712&partnerID=8YFLogxK
U2 - 10.1093/hmg/dds064
DO - 10.1093/hmg/dds064
M3 - Article
SN - 0964-6906
VL - 21
SP - 2497
EP - 2502
JO - Human molecular genetics
JF - Human molecular genetics
IS - 11
M1 - dds064
ER -
