Research ExplorerPublicationsHot-spot KIF5A mutations cause familial ALS

Hot-spot KIF5A mutations cause familial ALS

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Hot-spot KIF5A mutations cause familial ALS. / Brenner, David; Yilmaz, Rüstem; Müller, Kathrin; Grehl, Torsten; Petri, Susanne; Meyer, Thomas; Grosskreutz, Julian; Weydt, Patrick; Ruf, Wolfgang; Neuwirth, Christoph; Weber, Markus; Pinto, Susana; Claeys, Kristl G; Schrank, Berthold; Jordan, Berit; Knehr, Antje; Günther, Kornelia; Hübers, Annemarie; Zeller, Daniel; Kubisch, Christian; Jablonka, Sibylle; Sendtner, Michael; Klopstock, Thomas; de Carvalho, Mamede; Sperfeld, Anne; Borck, Guntram; Volk, Alexander E; Dorst, Johannes; Weis, Joachim; Otto, Markus; Schuster, Joachim; Del Tredici, Kelly; Braak, Heiko; Danzer, Karin M; Freischmidt, Axel; Meitinger, Thomas; Strom, Tim M; Ludolph, Albert C; Andersen, Peter M; Weishaupt, Jochen H; German ALS network MND-NET.

In: BRAIN, Vol. 141, No. 3, 01.03.2018, p. 688-697.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Brenner, D, Yilmaz, R, Müller, K, Grehl, T, Petri, S, Meyer, T, Grosskreutz, J, Weydt, P, Ruf, W, Neuwirth, C, Weber, M, Pinto, S, Claeys, KG, Schrank, B, Jordan, B, Knehr, A, Günther, K, Hübers, A, Zeller, D, Kubisch, C, Jablonka, S, Sendtner, M, Klopstock, T, de Carvalho, M, Sperfeld, A, Borck, G, Volk, AE, Dorst, J, Weis, J, Otto, M, Schuster, J, Del Tredici, K, Braak, H, Danzer, KM, Freischmidt, A, Meitinger, T, Strom, TM, Ludolph, AC, Andersen, PM, Weishaupt, JH & German ALS network MND-NET 2018, 'Hot-spot KIF5A mutations cause familial ALS', BRAIN, vol. 141, no. 3, pp. 688-697. https://doi.org/10.1093/brain/awx370

APA

Brenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S., Meyer, T., Grosskreutz, J., Weydt, P., Ruf, W., Neuwirth, C., Weber, M., Pinto, S., Claeys, K. G., Schrank, B., Jordan, B., Knehr, A., Günther, K., Hübers, A., Zeller, D., ... German ALS network MND-NET (2018). Hot-spot KIF5A mutations cause familial ALS. BRAIN, 141(3), 688-697. https://doi.org/10.1093/brain/awx370

Vancouver

Brenner D, Yilmaz R, Müller K, Grehl T, Petri S, Meyer T et al. Hot-spot KIF5A mutations cause familial ALS. BRAIN. 2018 Mar 1;141(3):688-697. https://doi.org/10.1093/brain/awx370

Bibtex

@article{fc2cccc44e7c4d4ca7de44c69c5f48ae,
title = "Hot-spot KIF5A mutations cause familial ALS",
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 = "Journal Article",
author = "David Brenner and R{\"u}stem Yilmaz and Kathrin M{\"u}ller and Torsten Grehl and Susanne Petri and Thomas Meyer and Julian Grosskreutz and Patrick Weydt and Wolfgang Ruf and Christoph Neuwirth and Markus Weber and Susana Pinto and Claeys, {Kristl G} and Berthold Schrank and Berit Jordan and Antje Knehr and Kornelia G{\"u}nther and Annemarie H{\"u}bers and Daniel Zeller and Christian Kubisch and Sibylle Jablonka and Michael Sendtner and Thomas Klopstock and {de Carvalho}, Mamede and Anne Sperfeld and Guntram Borck and Volk, {Alexander E} and Johannes Dorst and Joachim Weis and Markus Otto and Joachim Schuster and {Del Tredici}, Kelly and Heiko Braak and Danzer, {Karin M} and Axel Freischmidt and Thomas Meitinger and Strom, {Tim M} and Ludolph, {Albert C} and Andersen, {Peter M} and Weishaupt, {Jochen H} and {German ALS network MND-NET}",
note = "{\textcopyright} The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2018",
month = mar,
day = "1",
doi = "10.1093/brain/awx370",
language = "English",
volume = "141",
pages = "688--697",
journal = "BRAIN",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "3",

}

RIS

TY - JOUR

T1 - Hot-spot KIF5A mutations cause familial ALS

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

AU - Meitinger, Thomas

AU - Strom, Tim M

AU - Ludolph, Albert C

AU - Andersen, Peter M

AU - Weishaupt, Jochen H

AU - German ALS network MND-NET

N1 - © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

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% 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.

KW - Journal Article

U2 - 10.1093/brain/awx370

DO - 10.1093/brain/awx370

M3 - SCORING: Journal article

C2 - 29342275

VL - 141

SP - 688

EP - 697

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - 3

ER -