Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis

Abstract

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein.Morphogenesis in vertebrate organisms requires the integration of extracellular signals with alterations in the cellular cytoskeleton. Filamins regulate the organization of cytoskeletal F-actin into either parallel bundles or orthogonal gel networks 3 and also mediate interactions between subcortical actin networks and transmembrane receptors to modulate cell-cell, cell-matrix and intracytoplasmic signal transduction 1,2,4 . Mammals have three filamin genes, FLNA, FLNB and FLNC. FLNA and FLNB seem to be ubiquitously expressed 5,6 ; FLNC is predominantly expressed in muscle. Human filamin genes are highly similar with conserved exon-intron structure, and there is ∼70% homology at the protein level 2,7 . The filamin monomer comprises an N-terminal actin binding domain (ABD) followed by a series of 24 β-sheet repeats that collectively bind many cytoplasmic and transmembrane proteins 1,2 . Filamins exist in vivo as dimers. Dimerization, leading to homo-and possibly heterodimer formation, is mediated by interactions between C-terminal sequences 5,8,9 . Mutations in FLNA produce a spectrum of X-linked malformation and osteochondrodysplasia syndromes. FLNA loss-of-function mutations are usually embryonically lethal in males and underlie a neuronal migration disorder in females 10 . Mutations producing structural changes in the protein lead to numerous developmental anomalies in the brain, skeleton and viscera 11 .Recently the gene associated with SCT, an autosomal recessive disorder characterized by short stature and vertebral, carpal and tarsal fusions 12,13 , was localized on chromosome 3p14 (ref. 14). These studies and further recombination mapping (data not shown) identified a 4.7-cM candidate region, which included a 1.4-Mb region of homozygosity containing 14 genes. Mutations were not found in the candidate genes WNT5A 14 , ASB14 and IL17RD (also known as SEF) in affected individuals from the linked families. The gene FLNB localizes to this interval and, considering the r...

Filamin-regulated F-actin Assembly Is Essential for Morphogenesis and Controls Phototaxis in Dictyostelium

“…Furthermore, they are involved in signal transduction and interactions with several components of the NF B pathway and components of adhesion complexes, and the small GTPases RhoA, Rac1, Cdc42, and RalA have been reported to also interact with filamins (15,16). Mutations in the human FLNa gene are responsible for congenital malformations affecting multiple organ systems, presumably because of defective cell migration during embryonal development (17,18), and mutations in the FLNb gene cause skeletal malforma-tions (16,19). In Drosophila, filamin mutations affect oogenesis (20).…”

Filamin structure, function and mechanics: are altered filamin-mediated force responses associated with human disease?

“…FLNA missense mutations are associated with the otopalatodigital spectrum malformation disorders (OPD) primarily affecting skeletal development, clinically distinct from PH (Robertson et al 2003). In parallel, loss-of-function mutations in FLNB are associated with spondylocarpotarsal synostosis syndrome, and dominant gain-of-function missense mutations are associated with the atelosteogenesis group of skeletal malformation (Krakow et al 2004). The clinical distinction, mode of inheritance of the FLN gain-of-function phenotypes, FLN expression and increased actin binding activity of disease-associated mutant FLNs are consistent with a gain/alteration of FLN function mechanism for these disorders (Robertson et al 2003;Sawyer et al 2009;Clark et al 2009).…”

“…The clinical distinction, mode of inheritance of the FLN gain-of-function phenotypes, FLN expression and increased actin binding activity of disease-associated mutant FLNs are consistent with a gain/alteration of FLN function mechanism for these disorders (Robertson et al 2003;Sawyer et al 2009;Clark et al 2009). FLNB is highly localised along the human growth plate and in the cartilage of developing vertebrae (Krakow et al 2004), though the role that FLN plays in bone development remains unclear. The challenge now is to identify what properties of FLN are altered and the downstream consequences that lead to these diseases.…”

Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome

“…[2][3][4][5] The vast majority of patients show autosomal recessive inheritance with variants in the gene, FLNB, encoding the cytoskeleton protein filamin B. 6 We identified two families with dominant disease transmission: one with typical SCT previously reported by one of us 2 and the second with multiple pterygium syndrome (MPS; DA8) associated with skeletal manifestations. The present genetic study reveals that embryonic myosin heavy chain 3 (MYH3) mutations are associated with a spectrum of phenotypes including distal arthrogryposis (DA), MPS and SCT.…”