Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result (P = 1.84 × 10−8) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.

[1]  Xun Hu,et al.  Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6 , 2009, Science.

[2]  J L Haines,et al.  Supporting Online Material Materials and Methods Figs. S1 to S7 Tables S1 to S4 References Mutations in the Fus/tls Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis , 2022 .

[3]  R. Takahashi,et al.  Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3 , 2008, Neuroscience Research.

[4]  R. Ophoff,et al.  Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration , 2008, Human molecular genetics.

[5]  B. McConkey,et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis , 2008, Nature Genetics.

[6]  Xun Hu,et al.  TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis , 2008, Science.

[7]  Orla Hardiman,et al.  A genome-wide association study of sporadic ALS in a homogenous Irish population. , 2007, Human molecular genetics.

[8]  J. Schug.  Using TESS to Predict Transcription Factor Binding Sites in DNA Sequence , 2003, Current protocols in bioinformatics.

[9]  K. Mossman.  The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[10]  Frank Baas,et al.  Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis , 2008, Nature Genetics.

[11]  R. Ophoff,et al.  ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study , 2007, The Lancet Neurology.

[12]  T. Frayling.  Genome–wide association studies provide new insights into type 2 diabetes aetiology , 2007, Nature Reviews Genetics.

[13]  H. Harbo,et al.  Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis , 2007, Nature Genetics.

[14]  Silke Schmidt,et al.  Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosis , 2007, Nature Genetics.

[15]  S. Gabriel,et al.  Risk alleles for multiple sclerosis identified by a genomewide study. , 2007, The New England journal of medicine.

[16]  Kuixing Zhang,et al.  Whole-genome analysis of sporadic amyotrophic lateral sclerosis. , 2007, The New England journal of medicine.

[17]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[18]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[19]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[20]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[21]  Michael W. Pfaffl,et al.  Differential expression of molecular motors in the motor cortex of sporadic ALS , 2007, Neurobiology of Disease.

[22]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[23]  Sonja W. Scholz,et al.  Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data , 2007, The Lancet Neurology.

[24]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[25]  Sonja W. Scholz,et al.  Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. , 2007, Human molecular genetics.

[26]  J. Haines,et al.  Paraoxonase cluster polymorphisms are associated with sporadic ALS , 2006, Neurology.

[27]  M. Małecki,et al.  Paraoxonase gene polymorphisms and sporadic ALS , 2006, Neurology.

[28]  S. Ennis,et al.  ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis , 2006, Nature Genetics.

[29]  G. Abecasis,et al.  Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies , 2006, Nature Genetics.

[30]  When domestiques rebel: kinesins, cadherins and neuronal proliferation , 2005, Nature Cell Biology.

[31]  J. Connor,et al.  Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences , 2004, Journal of the Neurological Sciences.

[32]  T. Gillingwater,et al.  A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. , 2004, American journal of human genetics.

[33]  John W Griffin,et al.  DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). , 2004, American journal of human genetics.

[34]  Yasushi Hiraoka,et al.  Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport , 2003, Science.

[35]  Shin J. Oh,et al.  Mutant dynactin in motor neuron disease , 2003, Nature Genetics.

[36]  R. Urrutia,et al.  Sp1- and Krüppel-like transcription factors , 2003, Genome Biology.

[37]  P. Carmeliet,et al.  VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death , 2003, Nature Genetics.

[38]  M. Pericak-Vance,et al.  The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis , 2001, Nature Genetics.

[39]  S. Scherer,et al.  A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2 , 2001, Nature Genetics.

[40]  N. Hirokawa,et al.  Charcot-Marie-Tooth Disease Type 2A Caused by Mutation in a Microtubule Motor KIF1Bβ , 2001, Cell.

[41]  F. Baas,et al.  Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS , 2001, Neurology.

[42]  N. Hirokawa,et al.  Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. , 2001, Cell.

[43]  S. Hadano,et al.  A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2 , 2001, Nature Genetics.

[44]  J. Loeffler,et al.  Differential Screening of Mutated SOD1 Transgenic Mice Reveals Early Up-Regulation of a Fast Axonal Transport Component in Spinal Cord Motor Neurons , 2000, Neurobiology of Disease.

[45]  N. Hirokawa.  Stirring up Development with the Heterotrimeric Kinesin KIF3 , 2000, Traffic.

[46]  A. Malafosse,et al.  Association between centromeric deletions of the SMN gene and sporadic adult‐onset lower motor neuron disease , 1998, Annals of neurology.

[47]  H. Horvitz,et al.  Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis , 1997, Annals of neurology.

[48]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[49]  L. Kurland,et al.  Familial adult motor neuron disease: amyotrophic lateral sclerosis , 1986, Neurology.

[50]  W. Bradley,et al.  Amyotrophic leteral sclerosis: Part 2. Etiopathogenesis , 1985 .

[51]  W. Bradley,et al.  Amyotrophc Lateral Sclerosis: Part 1. Clinical Features, Pathology, and E h c d Issues in Management* , 2004 .