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Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis

Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis
Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11–positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
1946-6234
Smith, Bradley N.
d707ebcc-5728-47c9-a143-d6a5a2906055
Topp, Simon D.
1cde3b9d-f7d2-4b20-af4e-5c5f5d5e6748
Fallini, Claudia
17636797-7630-4c1b-872b-3735713bee49
Morrison, Karen
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
et al.
Smith, Bradley N.
d707ebcc-5728-47c9-a143-d6a5a2906055
Topp, Simon D.
1cde3b9d-f7d2-4b20-af4e-5c5f5d5e6748
Fallini, Claudia
17636797-7630-4c1b-872b-3735713bee49
Morrison, Karen
f00890f0-2fde-4dbd-a73b-7422e1b0ede8

Smith, Bradley N., Topp, Simon D. and Fallini, Claudia , et al. (2017) Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Science Translational Medicine, 9 (388), [eaad9157]. (doi:10.1126/scitranslmed.aad9157).

Record type: Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11–positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.

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Accepted/In Press date: 4 January 2017
e-pub ahead of print date: 3 May 2017
Published date: 3 May 2017

Identifiers

Local EPrints ID: 412898
URI: http://eprints.soton.ac.uk/id/eprint/412898
ISSN: 1946-6234
PURE UUID: 4f2c2abf-ab48-44e9-a88f-fc90dd68d751
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 07 Aug 2017 16:31
Last modified: 18 Feb 2021 17:26

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Contributors

Author: Bradley N. Smith
Author: Simon D. Topp
Author: Claudia Fallini
Author: Karen Morrison ORCID iD
Corporate Author: et al.

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