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

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

Structure of the ALS Mutation Target Annexin A11 Reveals a Stabilising N-Terminal Segment

“…The crystal structure of rat AnxA11 allows to analyse the structural basis of AnxA11 mutations linked to amyotrophic lateral sclerosis (ALS) [34] in humans. The sequence identity between full-length rat and human AnxA11 is 93.3%, being 96.5% for the core structure.…”

“…We studied the mutations thus far linked to ALS with respect to potential structural implications. Many of the mutations, including the best-characterised D40G [34], lie in the N-terminal extension, which is not present in the crystallised construct. The mutations in this region could affect protein-protein interactions, protein localisation, phase separation, or binding to mRNA [8].…”

“…Five mutations have thus far been described in ALS patients within the AnxA11 core: S229R, R235Q, R302C, R346C, and G491R; in addition, G189E is located two residues before the start of the crystallised rat AnxA11 construct [34,36]. In the 3D structure, the AnxA11 mutations can be observed clustered at two locations (Figure 5A).…”

Hitching a Ride: Mechanics of Organelle Transport Through Linker-Mediated Hitchhiking

“…Precise control of transport ranging over length scales from a few microns to tens of centimeters is achieved by regulating the interactions between moving and stationary cargo, motors, and other cytoskeletal structures. Defects in the regulation of organelle movement can lead to pathologies, particularly in long cells such as neurons, where axonal transport deficiencies have been implicated in neurodegenerative disorders including Alzheimer's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (1)(2)(3).…”

Enrichment of rare protein truncating variants in amyotrophic lateral sclerosis patients

“…Collecting sporadic case samples has been valuable for gene discovery in more common disorders such as schizophrenia (Singh et al, 2016), inflammatory bowel disease (Mohanan et al, 2018), and type 2 diabetes (Manning et al, 2017), and can have profound effects on the success of targeted therapeutic approaches Hamburg and Collins, 2010;Nelson et al, 2015). The most recent ALS genetic discoveries using large massively parallel sequencing data yielded several gene discoveries, TBK1, TUBA4A, ANXA11 and NEK1 and KIF5A (Cirulli et al, 2015;Kenna et al, 2016;Nicolas et al, 2018;Smith et al, 2014;Smith et al, 2017); in addition to other risk loci in C21orf2, MOBP, and SCFD1 (van Rheenen et al, 2016).…”