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@ARTICLE{Brenner:139838,
      author       = {Brenner, David and Yilmaz, Rüstem and Müller, Kathrin and
                      Grehl, Torsten and Petri, Susanne and Meyer, Thomas and
                      Grosskreutz, Julian and Weydt, Patrick and Ruf, Wolfgang and
                      Neuwirth, Christoph and Weber, Markus and Pinto, Susana and
                      Claeys, Kristl G and Schrank, Berthold and Jordan, Berit and
                      Knehr, Antje and Günther, Kornelia and Hübers, Annemarie
                      and Zeller, Daniel and Kubisch, Christian and Jablonka,
                      Sibylle and Sendtner, Michael and Klopstock, Thomas and de
                      Carvalho, Mamede and Sperfeld, Anne and Borck, Guntram and
                      Volk, Alexander E and Dorst, Johannes and Weis, Joachim and
                      Otto, Markus and Schuster, Joachim and Del Tredici, Kelly
                      and Braak, Heiko and Danzer, Karin M and Freischmidt,
                      Axel-Dieter and Meitinger, Thomas and Strom, Tim M and
                      Ludolph, Albert and Andersen, Peter M and Weishaupt, Jochen
                      H and MND-NET, German ALS network and Weyen, Ute and
                      Hermann, Andreas and Hagenacker, Tim and Koch, Jan Christoph
                      and Lingor, Paul and Göricke, Bettina and Zierz, Stephan
                      and Baum, Petra and Wolf, Joachim and Winkler, Andrea and
                      Young, Peter and Bogdahn, Ulrich and Prudlo, Johannes and
                      Kassubek, Jan},
      title        = {{H}ot-spot {KIF}5{A} mutations cause familial {ALS}.},
      journal      = {Brain},
      volume       = {141},
      number       = {3},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-06160},
      pages        = {688-697},
      year         = {2018},
      abstract     = {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.},
      keywords     = {Kinesins: genetics / Adult / Aged / Amyotrophic Lateral
                      Sclerosis: genetics / DNA Mutational Analysis / Family
                      Health / Female / Genetic Association Studies / Humans /
                      Kinesin: genetics / Lymphocytes: drug effects / Lymphocytes:
                      metabolism / Male / Middle Aged / Mutation: genetics / RNA,
                      Messenger: genetics / RNA, Messenger: metabolism / KIF5A
                      protein, human (NLM Chemicals) / RNA, Messenger (NLM
                      Chemicals) / Kinesin (NLM Chemicals)},
      cin          = {Clinical Dementia Research München},
      ddc          = {610},
      cid          = {I:(DE-2719)1111016},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29342275},
      pmc          = {pmc:PMC5837483},
      doi          = {10.1093/brain/awx370},
      url          = {https://pub.dzne.de/record/139838},
}