PUBLICATION
Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue
- Authors
- Marchica, V., Biasetti, L., Barnard, J., Li, S., Nikolaou, N., Frosch, M.P., Lucente, D.E., Eldaief, M., King, A., Fanto, M., Troakes, C., Houart, C., Smith, B.N.
- ID
- ZDB-PUB-240712-1
- Date
- 2024
- Source
- Brain : a journal of neurology 148(1): 276-290 (Journal)
- Registered Authors
- Houart, Corinne, Nikolaou, Nikolas
- Keywords
- amyotrophic lateral sclerosis, annexin A11, lamin B2, nuclear envelope
- MeSH Terms
-
- Humans
- Frontotemporal Dementia/genetics
- Frontotemporal Dementia/pathology
- Animals
- Male
- PubMed
- 38989900 Full text @ Brain
Abstract
Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small-alpha helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterised the phenotypes induced by a genetic loss of function (LoF) and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human WT Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterised by Lamin B2 mis-localisation. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS+/-FTD patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping