Filamin B mutations cause chondrocyte defects in skeletal development.

Filamin B mutations cause chondrocyte defects in skeletal development. Research Abstract Details 

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Filamin B mutations cause chondrocyte defects in skeletal development. Abstract Text:

Jie Lu,Gewei Lian,Robert Lenkinski,Alec De Grand,R Roy Vaid,Thomas Bryce,Marina Stasenko,Adele Boskey,Christopher Walsh,Volney Sheen,

Filamin B (FLNB) is a cytoplasmic protein that regulates the cytoskeletal network by cross-linking actin, linking cell membrane to the cytoskeleton and regulating intracellular signaling pathways responsible for skeletal development (Stossel, T.P., Condeelis, J., Cooley, L., Hartwig, J.H., Noegel, A., Schleicher, M. and Shapiro, S.S. (2001) Filamins as integrators of cell mechanics and signalling. Nat. Rev. Mol. Cell Biol., 2, 138-145). Mutations in FLNB cause human skeletal disorders [boomerang dysplasia, spondylocarpotarsal (SCT), Larsen, and atelosteogenesis I/III syndromes], which are characterized by disrupted vertebral segmentation, joint formation and endochondral ossification [Krakow, D., Robertson, S.P., King, L.M., Morgan, T., Sebald, E.T., Bertolotto, C., Wachsmann-Hogiu, S., Acuna, D., Shapiro, S.S., Takafuta, T. et al. (2004) Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat. Genet., 36, 405-410; Bicknell, L.S., Morgan, T., Bonafe, L., Wessels, M.W., Bialer, M.G., Willems, P.J., Cohn, D.H., Krakow, D. and Robertson, S.P. (2005) Mutations in FLNB cause boomerang dysplasia. J. Med. Genet., 42, e43]. Here we show that Flnb deficient mice have shortened distal limbs with small body size, and develop fusion of the ribs and vertebrae, abnormal spinal curvatures, and dysmorphic facial/calvarial bones, similar to the human phenotype. Characterization of the mutant mice demonstrated increased apoptosis along the bone periphery of the distal appendages, consistent with reduced bone width. No changes in the initial proliferative rate of chondrocytes were observed, but the progressive differentiation of chondrocyte precursors was impaired, consistent with reduced bone length. The extracellular matrix appeared disrupted and phosphorylated beta1-integrin (a collagen receptor and Flnb binding partner) expression was diminished in the mutant growth plate. Like integrin-deficient chondrocytes, adhesion to the ECM was decreased in Flnb(-/-) chondrocytes, and inhibition of beta1-integrin in these cells led to further impairments in cell spreading. These data suggest that disruption of the ECM-beta1-integrin-Flnb pathway contributes to defects in vertebral and distal limb development, similar to those seen in the human autosomal recessive SCT due to Flnb mutations.

Filamin B mutations cause chondrocyte defects in skeletal development. Publishing Authors By Initials

J Lu,G Lian,R Lenkinski,A De Grand,RR Vaid,T Bryce,M Stasenko,A Boskey,C Walsh,V Sheen,

For similar genetic phenomena: phenotype research abstracts see: genetic phenomena: phenotype research

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Filamin B mutations cause chondrocyte defects in skeletal development. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Human molecular genetics

VOLUME: 16

Page Numbers: 1661-75

Journal Abbreviation: Hum. Mol. Genet.

ISSN: 0964-6906

DAY: 17

MONTH: 05

YEAR: 2007

Filamin B mutations cause chondrocyte defects in skeletal development. Information

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LANGUAGE: eng

NlmUniqueID: 9208958

Filamin B mutations cause chondrocyte defects in skeletal development. Keywords Mesh Terms:

KEYWORDS: Phenotype

MESH TERMS: physiology

Chemical & Substance for Abstract: Filamin B mutations cause chondrocyte defects in skeletal development. Information

Substance Name: filamins

Registry Number: 0

Grant and Affiliation Information for Filamin B mutations cause chondrocyte defects in skeletal development.

AFFILIATION: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Country: England

AGENCY: United States NINDS

GRANT: 2R37 NS35129

ACRONYM: NS

MEDLINETA: Hum Mol Genet

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