STM—ANXA11是引起ALS的新致病基因

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.

1.Annexin A11 mutations identified in ALS patients after stringent filtering of exome sequencing data.

2.Annexin A11 immunohistochemical analysis in postmortem spinal cord tissue from a SALS case with the p.D40G mutation.

3.Transfection of WT and mutant annexin A11 into mouse primary motor neurons and HEK cells.

4.Annexin A11with the p.R235Qmutation sequestersWTannexinA11.

5.Annexin A11 mutations disrupt binding to calcyclin.