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Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development

Journal article
Authors Xianghua Zhou
Fei Tian
Johan Sandzen
R. Cao
E. Flaberg
L. Szekely
Y. Cao
Claes Ohlsson
Martin Bergö
Jan Borén
Levent Akyürek
Published in Proc Natl Acad Sci U S A
Volume 104
Issue 10
Pages 3919-24
ISSN 0027-8424 (Print)
Publication year 2007
Published at Wallenberg Laboratory
Institute of Medicine, Department of Internal Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 3919-24
Language en
Links www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Actins/metabolism, Animals, Bone and Bones/*physiology, Cell Movement, Chondrocytes/metabolism, Contractile Proteins/deficiency/*genetics/*physiology, Cytoplasm/metabolism, Endothelial Cells/metabolism, Fibroblasts/metabolism, Humans, Kyphosis/genetics, Mice, Mice, Knockout, *Microcirculation, Microfilament Proteins/deficiency/*genetics/*physiology, Scoliosis/genetics
Subject categories Medical and Health Sciences

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.

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