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Brain. 2018 Mar 1;141(3):688-697. doi: 10.1093/brain/awx370.

Hot-spot KIF5A mutations cause familial ALS.

Author information

1
Neurology Department, Ulm University, Ulm, Germany.
2
Department of Neurology, Alfried Krupp Hospital, Essen, Germany.
3
Department of Neurology, Hannover Medical School, Hannover, Germany.
4
Charité University Hospital, Humboldt-University, Berlin, Germany.
5
Department of Neurology, Jena University Hospital, Jena, Germany.
6
Department for Neurodegenerative Disorders and Gerontopsychiatry, Bonn University, Bonn, Germany.
7
Kantonsspital St. Gallen, ALS Outpatient Clinic, St. Gallen, Switzerland.
8
Department of Neurosciences and Mental Health, Hospital de Santa Maria-CHLN, Lisbon, Portugal.
9
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
10
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
11
Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany.
12
Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
13
Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Leuven, Belgium.
14
Department of Neurology, DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany.
15
Department of Neurology Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
16
Department of Neurology, University of Würzburg, Würzburg, Germany.
17
Institute of Human Genetics, Ulm University, Ulm, Germany.
18
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
19
Institute of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
20
Department of Neurology with Friedrich-Baur-Institute, University of Munich, Munich, Germany.
21
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
22
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
23
Instituto de Medicina Molecular and Institute of Physiology, Faculty of Medicine, University of Lisbon, Portugal.
24
SyNergy, Munich Cluster for Systems Neurology, Ludwig Maximilians Universität München, Germany.
25
Institute of Human Genetics, Technische Universität München, München, Germany.

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.

PMID:
29342275
PMCID:
PMC5837483
DOI:
10.1093/brain/awx370
[Indexed for MEDLINE]
Free PMC Article

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