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000139838 0247_ $$2doi$$a10.1093/brain/awx370
000139838 0247_ $$2pmid$$apmid:29342275
000139838 0247_ $$2pmc$$apmc:PMC5837483
000139838 0247_ $$2ISSN$$a0006-8950
000139838 0247_ $$2ISSN$$a1460-2156
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000139838 037__ $$aDZNE-2020-06160
000139838 041__ $$aEnglish
000139838 082__ $$a610
000139838 1001_ $$aBrenner, David$$b0
000139838 245__ $$aHot-spot KIF5A mutations cause familial ALS.
000139838 260__ $$aOxford$$bOxford Univ. Press$$c2018
000139838 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2018-01-12
000139838 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2018-03-01
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000139838 520__ $$aHeterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
000139838 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x0
000139838 542__ $$2Crossref$$i2018-01-12$$uhttp://creativecommons.org/licenses/by-nc/4.0/
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000139838 650_7 $$2NLM Chemicals$$aKIF5A protein, human
000139838 650_7 $$2NLM Chemicals$$aRNA, Messenger
000139838 650_7 $$0EC 3.6.4.4$$2NLM Chemicals$$aKinesin
000139838 650_2 $$2MeSH$$aKinesins: genetics
000139838 650_2 $$2MeSH$$aAdult
000139838 650_2 $$2MeSH$$aAged
000139838 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000139838 650_2 $$2MeSH$$aDNA Mutational Analysis
000139838 650_2 $$2MeSH$$aFamily Health
000139838 650_2 $$2MeSH$$aFemale
000139838 650_2 $$2MeSH$$aGenetic Association Studies
000139838 650_2 $$2MeSH$$aHumans
000139838 650_2 $$2MeSH$$aKinesin: genetics
000139838 650_2 $$2MeSH$$aLymphocytes: drug effects
000139838 650_2 $$2MeSH$$aLymphocytes: metabolism
000139838 650_2 $$2MeSH$$aMale
000139838 650_2 $$2MeSH$$aMiddle Aged
000139838 650_2 $$2MeSH$$aMutation: genetics
000139838 650_2 $$2MeSH$$aRNA, Messenger: genetics
000139838 650_2 $$2MeSH$$aRNA, Messenger: metabolism
000139838 7001_ $$aYilmaz, Rüstem$$b1
000139838 7001_ $$aMüller, Kathrin$$b2
000139838 7001_ $$aGrehl, Torsten$$b3
000139838 7001_ $$aPetri, Susanne$$b4
000139838 7001_ $$aMeyer, Thomas$$b5
000139838 7001_ $$aGrosskreutz, Julian$$b6
000139838 7001_ $$0P:(DE-HGF)0$$aWeydt, Patrick$$b7
000139838 7001_ $$0P:(DE-2719)9001522$$aRuf, Wolfgang$$b8$$udzne
000139838 7001_ $$aNeuwirth, Christoph$$b9
000139838 7001_ $$aWeber, Markus$$b10
000139838 7001_ $$aPinto, Susana$$b11
000139838 7001_ $$aClaeys, Kristl G$$b12
000139838 7001_ $$aSchrank, Berthold$$b13
000139838 7001_ $$aJordan, Berit$$b14
000139838 7001_ $$aKnehr, Antje$$b15
000139838 7001_ $$aGünther, Kornelia$$b16
000139838 7001_ $$0P:(DE-HGF)0$$aHübers, Annemarie$$b17
000139838 7001_ $$aZeller, Daniel$$b18
000139838 7001_ $$aKubisch, Christian$$b19
000139838 7001_ $$aJablonka, Sibylle$$b20
000139838 7001_ $$aSendtner, Michael$$b21
000139838 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b22
000139838 7001_ $$ade Carvalho, Mamede$$b23
000139838 7001_ $$aSperfeld, Anne$$b24
000139838 7001_ $$aBorck, Guntram$$b25
000139838 7001_ $$aVolk, Alexander E$$b26
000139838 7001_ $$aDorst, Johannes$$b27
000139838 7001_ $$aWeis, Joachim$$b28
000139838 7001_ $$aOtto, Markus$$b29
000139838 7001_ $$aSchuster, Joachim$$b30
000139838 7001_ $$aDel Tredici, Kelly$$b31
000139838 7001_ $$aBraak, Heiko$$b32
000139838 7001_ $$0P:(DE-2719)9001513$$aDanzer, Karin M$$b33$$udzne
000139838 7001_ $$0P:(DE-2719)9001054$$aFreischmidt, Axel-Dieter$$b34$$udzne
000139838 7001_ $$0P:(DE-2719)9000207$$aMeitinger, Thomas$$b35$$udzne
000139838 7001_ $$aStrom, Tim M$$b36
000139838 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert$$b37$$udzne
000139838 7001_ $$aAndersen, Peter M$$b38
000139838 7001_ $$0P:(DE-2719)9000455$$aWeishaupt, Jochen H$$b39$$eCorresponding author$$udzne
000139838 7001_ $$aMND-NET, German ALS network$$b40
000139838 7001_ $$aWeyen, Ute$$b41
000139838 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b42$$udzne
000139838 7001_ $$aHagenacker, Tim$$b43
000139838 7001_ $$aKoch, Jan Christoph$$b44
000139838 7001_ $$0P:(DE-2719)2812561$$aLingor, Paul$$b45$$udzne
000139838 7001_ $$aGöricke, Bettina$$b46
000139838 7001_ $$aZierz, Stephan$$b47
000139838 7001_ $$aBaum, Petra$$b48
000139838 7001_ $$aWolf, Joachim$$b49
000139838 7001_ $$aWinkler, Andrea$$b50
000139838 7001_ $$aYoung, Peter$$b51
000139838 7001_ $$aBogdahn, Ulrich$$b52
000139838 7001_ $$0P:(DE-2719)2380559$$aPrudlo, Johannes$$b53$$udzne
000139838 7001_ $$aKassubek, Jan$$b54
000139838 77318 $$2Crossref$$3journal-article$$a10.1093/brain/awx370$$b : Oxford University Press (OUP), 2018-01-12$$n3$$p688-697$$tBrain$$v141$$x0006-8950$$y2018
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000139838 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837483
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000139838 999C5 $$2Crossref$$oAndersen 2005$$y2005
000139838 999C5 $$2Crossref$$oAndersen 2012$$y2012
000139838 999C5 $$2Crossref$$oBraak 2013$$y2013
000139838 999C5 $$2Crossref$$oBraak 2017$$y2017
000139838 999C5 $$2Crossref$$oBrenner 2016$$y2016
000139838 999C5 $$2Crossref$$oBrettschneider 2014$$y2014
000139838 999C5 $$2Crossref$$oCelniker 2002$$y2002
000139838 999C5 $$2Crossref$$oChiò 2009$$y2009
000139838 999C5 $$2Crossref$$oDeng 2011$$y2011
000139838 999C5 $$2Crossref$$oDuis 2016$$y2016
000139838 999C5 $$2Crossref$$oFagerberg 2014$$y2014
000139838 999C5 $$2Crossref$$oFiglewicz 1994$$y1994
000139838 999C5 $$2Crossref$$oFreischmidt 2015$$y2015
000139838 999C5 $$2Crossref$$oGitcho 2008$$y2008
000139838 999C5 $$2Crossref$$oGoizet 2009$$y2009
000139838 999C5 $$2Crossref$$oGros-Louis 2004$$y2004
000139838 999C5 $$2Crossref$$oGuinto 2017$$y2017
000139838 999C5 $$2Crossref$$oHerder 2013$$y2013
000139838 999C5 $$2Crossref$$oHirokawa 2009$$y2009
000139838 999C5 $$2Crossref$$oKaji 2016$$y2016
000139838 999C5 $$2Crossref$$oKenna 2016$$y2016
000139838 999C5 $$2Crossref$$oKimonis 2008$$y2008
000139838 999C5 $$2Crossref$$oKühnlein 2008$$y2008
000139838 999C5 $$2Crossref$$oLek 2016$$y2016
000139838 999C5 $$2Crossref$$oLivak 2001$$y2001
000139838 999C5 $$2Crossref$$oLiu 2014$$y2014
000139838 999C5 $$2Crossref$$oMcLaughlin 2017$$y2017
000139838 999C5 $$2Crossref$$oMorais 2017$$y2017
000139838 999C5 $$2Crossref$$oNakajima 2012$$y2012
000139838 999C5 $$2Crossref$$oNguyen 2018$$y2018
000139838 999C5 $$2Crossref$$oNiclas 1994$$y1994
000139838 999C5 $$2Crossref$$oÖrlén 2009$$y2009
000139838 999C5 $$2Crossref$$oPuls 2003$$y2003
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000139838 999C5 $$2Crossref$$oReid 2002$$y2002
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