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

Sci Transl Med
Authors
Keywords
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 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 ( = 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 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 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.

Year of Publication
2017
Journal
Sci Transl Med
Volume
9
Issue
388
Date Published
2017 05 03
ISSN
1946-6242
DOI
10.1126/scitranslmed.aad9157
PubMed ID
28469040
Links
Grant list
Medical Research Council / United Kingdom
Wellcome Trust / United Kingdom
HHMI / Howard Hughes Medical Institute / United States
R01 NS073873 / NS / NINDS NIH HHS / United States