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.
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Acknowledgements
We thank all the families who participated in this research; M. Priore, G. Rose and F. Field of the International Skeletal Dysplasia Registry for their assistance in collecting the families; N. Ehtesham for her assistance with preparing the figures; and K. Lyons for discussions regarding the expression of filamin B during mouse development. This work was supported in part by grants from the US National Institute of Health (to D.H.C., D.K. and D.L.R.), the Cedars-Sinai General Clinical Research Center, the Drown Foundation (to D.K.) and the National Organization for Rare Disorders (to J.M.G.). D.H.C. is the recipient of a Winnick Family Foundation Clinical Scholars award. S.P.R. and T.M. are supported by the Child Health Research Foundation of New Zealand.
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Krakow, D., Robertson, S., King, L. et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 36, 405–410 (2004). https://doi.org/10.1038/ng1319
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DOI: https://doi.org/10.1038/ng1319
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