%0 Journal Article
%T Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue.
%A Marchica V
%A Biasetti L
%A Barnard J
%A Li S
%A Nikolaou N
%A Frosch MP
%A Lucente DE
%A Eldaief M
%A King A
%A Fanto M
%A Troakes C
%A Houart C
%A Smith BN
%J Brain
%V 0
%N 0
%D 2024 Jul 11
%M 38989900
%F 15.255
%R 10.1093/brain/awae226
%X 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.