TY  - JOUR
AU  - Brenner, David
AU  - Yilmaz, Rüstem
AU  - Müller, Kathrin
AU  - Grehl, Torsten
AU  - Petri, Susanne
AU  - Meyer, Thomas
AU  - Grosskreutz, Julian
AU  - Weydt, Patrick
AU  - Ruf, Wolfgang
AU  - Neuwirth, Christoph
AU  - Weber, Markus
AU  - Pinto, Susana
AU  - Claeys, Kristl G
AU  - Schrank, Berthold
AU  - Jordan, Berit
AU  - Knehr, Antje
AU  - Günther, Kornelia
AU  - Hübers, Annemarie
AU  - Zeller, Daniel
AU  - Kubisch, Christian
AU  - Jablonka, Sibylle
AU  - Sendtner, Michael
AU  - Klopstock, Thomas
AU  - de Carvalho, Mamede
AU  - Sperfeld, Anne
AU  - Borck, Guntram
AU  - Volk, Alexander E
AU  - Dorst, Johannes
AU  - Weis, Joachim
AU  - Otto, Markus
AU  - Schuster, Joachim
AU  - Del Tredici, Kelly
AU  - Braak, Heiko
AU  - Danzer, Karin M
AU  - Freischmidt, Axel-Dieter
AU  - Meitinger, Thomas
AU  - Strom, Tim M
AU  - Ludolph, Albert
AU  - Andersen, Peter M
AU  - Weishaupt, Jochen H
AU  - MND-NET, German ALS network
AU  - Weyen, Ute
AU  - Hermann, Andreas
AU  - Hagenacker, Tim
AU  - Koch, Jan Christoph
AU  - Lingor, Paul
AU  - Göricke, Bettina
AU  - Zierz, Stephan
AU  - Baum, Petra
AU  - Wolf, Joachim
AU  - Winkler, Andrea
AU  - Young, Peter
AU  - Bogdahn, Ulrich
AU  - Prudlo, Johannes
AU  - Kassubek, Jan
TI  - Hot-spot KIF5A mutations cause familial ALS.
JO  - Brain
VL  - 141
IS  - 3
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-06160
SP  - 688-697
PY  - 2018
AB  - 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
KW  - Kinesins: genetics
KW  - Adult
KW  - Aged
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - DNA Mutational Analysis
KW  - Family Health
KW  - Female
KW  - Genetic Association Studies
KW  - Humans
KW  - Kinesin: genetics
KW  - Lymphocytes: drug effects
KW  - Lymphocytes: metabolism
KW  - Male
KW  - Middle Aged
KW  - Mutation: genetics
KW  - RNA, Messenger: genetics
KW  - RNA, Messenger: metabolism
KW  - KIF5A protein, human (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Kinesin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29342275
C2  - pmc:PMC5837483
DO  - DOI:10.1093/brain/awx370
UR  - https://pub.dzne.de/record/139838
ER  -