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
-
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/pathology
- Spinal Cord/metabolism
- Spinal Cord/pathology
- Animals
- Annexins*/genetics
- Annexins*/metabolism
- Frontotemporal Dementia/genetics
- Frontotemporal Dementia/pathology
- Lamin Type B/genetics
- Lamin Type B/metabolism
- Male
- Nuclear Envelope*/genetics
- Nuclear Envelope*/metabolism
- Zebrafish*
- Mutation*
- Humans
- PubMed
- 38989900 Full text @ Brain
Citation
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. (2024) Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue. Brain : a journal of neurology. 148(1):276-290.
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