{Reference Type}: Journal Article
{Title}: Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue.
{Author}: Marchica V;Biasetti L;Barnard J;Li S;Nikolaou N;Frosch MP;Lucente DE;Eldaief M;King A;Fanto M;Troakes C;Houart C;Smith BN;
{Journal}: Brain
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jul 11
{Factor}: 15.255
{DOI}: 10.1093/brain/awae226
{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.