139838 20240321220708.0 10.1093/brain/awx370 doi pmid:29342275 pmid pmc:PMC5837483 pmc 0006-8950 ISSN 1460-2156 ISSN altmetric:31582036 altmetric DZNE-2020-06160 English 610 Brenner, David 0 Hot-spot KIF5A mutations cause familial ALS. Oxford 2018 Oxford Univ. Press online Crossref Oxford University Press (OUP) 2018-01-12 print Crossref Oxford University Press (OUP) 2018-03-01 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1631197322_23921 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Heterozygous 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. 344 - Clinical and Health Care Research (POF3-344) G:(DE-HGF)POF3-344 POF3-344 POF III 0 2018-01-12 Crossref http://creativecommons.org/licenses/by-nc/4.0/ Dataset connected to CrossRef, PubMed, KIF5A protein, human NLM Chemicals RNA, Messenger NLM Chemicals Kinesin EC 3.6.4.4 NLM Chemicals Kinesins: genetics MeSH Adult MeSH Aged MeSH Amyotrophic Lateral Sclerosis: genetics MeSH DNA Mutational Analysis MeSH Family Health MeSH Female MeSH Genetic Association Studies MeSH Humans MeSH Kinesin: genetics MeSH Lymphocytes: drug effects MeSH Lymphocytes: metabolism MeSH Male MeSH Middle Aged MeSH Mutation: genetics MeSH RNA, Messenger: genetics MeSH RNA, Messenger: metabolism MeSH Yilmaz, Rüstem 1 Müller, Kathrin 2 Grehl, Torsten 3 Petri, Susanne 4 Meyer, Thomas 5 Grosskreutz, Julian 6 Weydt, Patrick P:(DE-HGF)0 7 Ruf, Wolfgang P:(DE-2719)9001522 8 dzne Neuwirth, Christoph 9 Weber, Markus 10 Pinto, Susana 11 Claeys, Kristl G 12 Schrank, Berthold 13 Jordan, Berit 14 Knehr, Antje 15 Günther, Kornelia 16 Hübers, Annemarie P:(DE-HGF)0 17 Zeller, Daniel 18 Kubisch, Christian 19 Jablonka, Sibylle 20 Sendtner, Michael 21 Klopstock, Thomas P:(DE-2719)2810704 22 de Carvalho, Mamede 23 Sperfeld, Anne 24 Borck, Guntram 25 Volk, Alexander E 26 Dorst, Johannes 27 Weis, Joachim 28 Otto, Markus 29 Schuster, Joachim 30 Del Tredici, Kelly 31 Braak, Heiko 32 Danzer, Karin M P:(DE-2719)9001513 33 dzne Freischmidt, Axel-Dieter P:(DE-2719)9001054 34 dzne Meitinger, Thomas P:(DE-2719)9000207 35 dzne Strom, Tim M 36 Ludolph, Albert P:(DE-2719)2812633 37 dzne Andersen, Peter M 38 Weishaupt, Jochen H P:(DE-2719)9000455 39 Corresponding author dzne MND-NET, German ALS network 40 Weyen, Ute 41 Hermann, Andreas P:(DE-2719)2811732 42 dzne Hagenacker, Tim 43 Koch, Jan Christoph 44 Lingor, Paul P:(DE-2719)2812561 45 dzne Göricke, Bettina 46 Zierz, Stephan 47 Baum, Petra 48 Wolf, Joachim 49 Winkler, Andrea 50 Young, Peter 51 Bogdahn, Ulrich 52 Prudlo, Johannes P:(DE-2719)2380559 53 dzne Kassubek, Jan 54 10.1093/brain/awx370 : Oxford University Press (OUP), 2018-01-12 3 688-697 journal-article Crossref Brain 141 2018 0006-8950 10.1093/brain/awx370 Vol. 141, no. 3, p. 688 - 697 PERI:(DE-600)1474117-9 3 141:3<688 - 697 688-697 Brain 141 2018 0006-8950 Pubmed Central http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837483 VDB oai:pub.dzne.de:139838 External Institute I:(DE-HGF)0 Extern 8 P:(DE-2719)9001522 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 22 P:(DE-2719)2810704 External Institute I:(DE-HGF)0 Extern 33 P:(DE-2719)9001513 External Institute I:(DE-HGF)0 Extern 34 P:(DE-2719)9001054 External Institute I:(DE-HGF)0 Extern 35 P:(DE-2719)9000207 External Institute I:(DE-HGF)0 Extern 37 P:(DE-2719)2812633 External Institute I:(DE-HGF)0 Extern 39 P:(DE-2719)9000455 External Institute I:(DE-HGF)0 Extern 42 P:(DE-2719)2811732 External Institute I:(DE-HGF)0 Extern 45 P:(DE-2719)2812561 External Institute I:(DE-HGF)0 Extern 53 P:(DE-2719)2380559 DE-HGF Gesundheit Erkrankungen des Nervensystems G:(DE-HGF)POF3-340 G:(DE-HGF)POF3-344 G:(DE-HGF)POF3 G:(DE-HGF)POF3-300 G:(DE-HGF)POF Clinical and Health Care Research 0 2018 Nationallizenz StatID:(DE-HGF)0420 StatID 2022-11-09 ger DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-09 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-09 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-09 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-09 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-09 DBCoverage StatID:(DE-HGF)1110 StatID Current Contents - 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