Title: Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity
Authors: Daniel, Philip B ×
Morgan, Tim
Alanay, Yasemin
Bijlsma, Emilia
Cho, Tae-Joon
Cole, Trevor
Collins, Felicity
David, Albert
Devriendt, Koenraad
Faivre, Laurence
Ikegawa, Shiro
Jacquemont, Sebastien
Jesic, Milos
Krakow, Deborah
Liebrecht, Daniela
Maitz, Silvia
Marlin, Sandrine
Morin, Gilles
Nishikubo, Toshiya
Nishimura, Gen
Prescott, Trine
Scarano, Gioacchino
Shafeghati, Yousef
Skovby, Flemming
Tsutsumi, Seiji
Whiteford, Margo
Zenker, Martin
Robertson, Stephen P #
Issue Date: Apr-2012
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:33 issue:4 pages:665-673
Article number: 10.1002/humu.22012
Abstract: Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as ABD mutations, demonstrated that with only one exception disease-associated substitutions surrounding hinge 1 demonstrated no tendency to form actin-filamin foci. The exception, a substitution in filamin repeat 6, lies within a region previously implicated in filamin-actin binding. These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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