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ALS Associated With Defects in Vesicular Trafficking Protein

NEW YORK (GenomeWeb) – An international team led by investigators in the UK, US, and Japan has identified a gene impacted by rare mutations in a subset of individuals with familial or sporadic amyotrophic lateral sclerosis (ALS).

As they reported in Science Translational Medicine today, the researchers used exome sequencing and bioinformatic analyses on families affected by ALS to track down a rare mutation in the annexin A11-coding gene ANXA11. The same alteration turned up in a case of sporadic ALS as well, while subsequent analyses on familial and sporadic cases led to a total of half a dozen ALS-associated mutations in ANXA11.

"[W]e have identified six rare ANXA11 variants in 13 individuals, which account for [approximately 1 percent] of familial and 1.7 percent of apparent [sporadic ALS] cases in our cohort," corresponding author Christopher Shaw, a researcher with the King's College London United Kingdom Dementia Research Institute Centre, and his co-authors wrote.

Annexin A11 is a calcium-dependent phospholipid-binding protein that is involved in intracellular vesicle trafficking.

A handful of ALS risk genes have already been identified through past studies, the team noted, ranging from non-synonymous mutations or rare variants in genes such as SOD1 or NEK1, respectively, to repeat expansions affecting C9orf72.

For their new study, the investigators sequenced the exomes of 751 individuals of European ancestry with familial ALS who had tested negative for the C9orf72 expansions, including members of 50 ALS-affected families.

Along with mutations in known ALS risk genes such as SOD1, FUS, or TUBA4A, the team identified a candidate mutation in ANXA11 in two families from the UK and one affected individual from Italy — findings supported by a subsequent analysis of almost 700 unrelated individuals with familial ALS.

The researchers identified the same rare change in ANXA11 in another individual when they performed targeted sequencing on another 180 individuals with sporadic ALS. All told, they found six individuals with the original mutation and five other rare ANXA11 mutations that turned up across four familial and two sporadic ALS cases.

In addition to looking at shared features in ALS cases involving ANXA11 mutations — such as relatively late disease onset and some shared spinal cord features — the team went on to do follow-up experiments in patient samples, post-mortem tissue samples, and human and mouse cell lines to tease apart the consequences of such alterations.

Preliminary results from the analyses hint that ALS-associated mutations in ANXA11 may upset the typical binding activity of the protein it encodes, the authors explained, leading to problematic protein conglomerates. "ANXA11 variants altered binding to calcyclin," they wrote, "which led to aggregation of annexin A11 in the cytoplasm of transfected cells and in neuronal cytoplasmic inclusions in postmortem spinal cord and brain tissue from ALS patients."