title: Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development.
abstract: Mutations in filamin B (FLNB), a gene encoding a cytoplasmic actin-binding protein, have been found in human skeletal disorders, including boomerang dysplasia, spondylocarpotarsal syndrome, Larsen syndrome, and atelosteogenesis phenotypes I and III. To examine the role of FLNB in vivo, we generated mice with a targeted disruption of Flnb. Fewer than 3% of homozygous embryos reached term, indicating that Flnb is important in embryonic development. Heterozygous mutant mice were indistinguishable from their wild-type siblings. Flnb was ubiquitously expressed; strong expression was found in endothelial cells and chondrocytes. Flnb-deficient fibroblasts exhibited more disorganized formation of actin filaments and reduced ability to migrate compared with wild-type controls. Flnb-deficient embryos exhibited impaired development of the microvasculature and skeletal system. The few Flnb-deficient mice that were born were very small and had severe skeletal malformations, including scoliotic and kyphotic spines, lack of intervertebral discs, fusion of vertebral bodies, and reduced hyaline matrix in extremities, thorax, and vertebrae. These mice died or had to be euthanized before 4 weeks of age. Thus, the phenotypes of Flnb-deficient mice closely resemble those of human skeletal disorders with mutations in FLNB.
authors.affiliation: Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Göteborg University, SE 413 45 Göteborg, Sweden.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Zhou
authors.forename: Fei
authors.initials: F
authors.lastname: Tian
authors.forename: Johan
authors.initials: J
authors.lastname: Sandzén
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Emilie
authors.initials: E
authors.lastname: Flaberg
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szekely
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Levent M
authors.initials: LM
authors.lastname: Akyürek
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000502:physiology*; D002465:Cell Movement; D019902:Chondrocytes / Q000378:metabolism; D003285:Contractile Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D064448:Filamins; D006801:Humans; D007738:Kyphosis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D012600:Scoliosis / Q000235:genetics
chemical_list: D000199:Actins; D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins