Mutations in the filamin B (FLNB) gene cause several skeletal disorders (Larsen syndrome, Atelosteogenesis and Boomerang displasia). In this issue, Daniel et al. (Hum Mutat 33:665–673, 2012)) perform genotype-phenotype correlation studies on individuals with LS-AO-BD spectrum disorders and find that FLNB mutations cluster in non-random fashion in exons encoding the calpain homology 2 (CH2) portion of the actin-binding domain (ABD) and repeats 14-17 that flank the hinge 1 region (H1). They transiently over-express several full-length FLNB constructs containing either the ABD or peri-H1 mutations and show that FLNB ABD mutant proteins co-localize with actin in cytoplasmic focal accumulations. The degree of accumulation correlates with disease severity. The authors, however, find that two of three peri-H1 mutations do not lead to actin-filamin focal accumulations. These findings suggest two different pathogenic mechanisms giving rise to this spectrum disorder: disruption of actin dynamics through FLNB ABD mutations and presumptive alteration of filamin mechanosensory properties through FLNB peri-H1 mutations.
It remains to be seen if focal accumulations are found in human patients, whether they are disease causing structures, and how they might affect disease pathogenesis. The focal accumulations might comprise part of the actin cap structure and their peri-nuclear localization suggests some role in Golgi function or cytoplasm-nuclear transduction. While the CH2 mutations presumably alter actin turnover, it is unclear how changes in actin dynamics lead to accumulations and cause the skeletal phenotypes. Less is known of the pathogenesis involving the peri-H1 region, but this domain may effect FLNB conformation and also alter its actin-dependent functions.