Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome

Abstract

Spondylocarpotarsal synostosis syndrome (SCT) is an autosomal recessive disease that is characterized by short stature, and fusions of the vertebrae and carpal and tarsal bones. SCT results from homozygosity or compound heterozygosity for nonsense mutations in FLNB. FLNB encodes filamin B, a multifunctional cytoplasmic protein that plays a critical role in skeletal development. Protein extracts derived from cells of SCT patients with nonsense mutations in FLNB did not contain filamin B, demonstrating that SCT results from absence of filamin B. To understand the role of filamin B in skeletal development, an Flnb-/- mouse model was generated. The Flnb-/- mice were phenotypically similar to individuals with SCT as they exhibited short stature and similar skeletal abnormalities. Newborn Flnb-/- mice had fusions between the neural arches of the vertebrae in the cervical and thoracic spine. At postnatal day 60, the vertebral fusions were more widespread and involved the vertebral bodies as well as the neural arches. In addition, fusions were seen in sternum and carpal bones. Analysis of the Flnb-/- mice phenotype showed that an absence of filamin B causes progressive vertebral fusions, which is contrary to the previous hypothesis that SCT results from failure of normal spinal segmentation. These findings suggest that spinal segmentation can occur normally in the absence of filamin B, but the protein is required for maintenance of intervertebral, carpal and sternal joints, and the joint fusion process commences antenatally.

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

“…This finding is interesting as Flnb knockout mice show impaired development of the microvasculature and skeletal system with bone and joint fusions [18,19]. This also suggests a link between A-to-I editing of the Flnb transcript and the main function of the encoded protein.…”

“…MIM Number: *300017 and *603381, respectively). This difference is mirrored in the mouse, where the deletion of the Flna gene causes lethal heart and vascular defects [16,17] while the deletion of the Flnb gene leads to lethal skeletal malformations with bone fusions [18,19]. …”

Whole-genome sequence analyses of Western Central African Pygmy hunter-gatherers reveal a complex demographic history and identify candidate genes under positive natural selection

“…The gene FLNB in the first region (locus: Chr 3: 57918877-58055004) encodes filamin B, a multifunctional cytoplasmic protein that plays a critical role in skeletal development. Flnb knockout mice are phenotypically similar to individuals with spondylocarpotarsal syndrome as they exhibited short stature and similar skeletal abnormalities (Farrington-Rock et al 2008). FLNB is known to be associated with height in African Pygmies (Jarvis et al 2012;Lachance et al 2012) and has also been reported to be associated with osteoporosis in women (Wilson et al 2009).…”

Filamin B Plays a Key Role in Vascular Endothelial Growth Factor-induced Endothelial Cell Motility through Its Interaction with Rac-1 and Vav-2

“…High levels of filamin A and filamin B have previously been detected in vessels (15)(16)(17) and in endothelial cells in culture (17)(18)(19). Knock-out experiments show the functional importance of each isoform: filamin A knock-out mice die during development due to aberrant vascular patterning and cardiac defects (20,21), whereas filamin B deficiency in mice mainly causes skeletal malformations (22)(23)(24) and vascular deficiencies (23).…”