Preprint: hyperactivating mutation in formin-like 2 gene causes brain and vertebral defects in mice

Researchers have posted a preprint to bioRxiv reporting the identification and characterisation of a mouse strain, designated nmf418, carrying a homozygous mutation in the splice acceptor of the Fmnl2 gene. Fmnl2 encodes formin-like protein 2, a member of the formin family of proteins that nucleate and elongate actin filaments to regulate cell morphology and migration.

The nmf418 mutation causes exon skipping in Fmnl2, which the authors show produces a hyperactivating effect on the encoded protein — meaning the mutant protein has enhanced actin-polymerising activity compared with the wild-type. Affected mice display hindlimb motor dysfunction, enlarged midbrain colliculi, cerebellar hypoplasia (reduced cerebellar size), and vertebral abnormalities in the thoracolumbar region of the spinal cord.

Formins as a gene family have been linked to a spectrum of human conditions, including kidney disease and non-syndromic intellectual disability. The Fmnl2 gene in particular has not previously been associated with brain or vertebral development defects via a hyperactivating mechanism, making this finding of potential relevance to understanding the range of diseases caused by dysregulated actin cytoskeleton dynamics.

This work has not yet been peer-reviewed. The findings are based on a mouse model and do not directly establish causation in human disease.