title: Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity.
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.
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Daniel
authors.forename: Tim
authors.initials: T
authors.lastname: Morgan
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Emilia
authors.initials: E
authors.lastname: Bijlsma
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Felicity
authors.initials: F
authors.lastname: Collins
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Milos
authors.initials: M
authors.lastname: Jesic
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Daniela
authors.initials: D
authors.lastname: Liebrecht
authors.forename: Silvia
authors.initials: S
authors.lastname: Maitz
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Gilles
authors.initials: G
authors.lastname: Morin
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nishikubo
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Trine
authors.initials: T
authors.lastname: Prescott
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Yousef
authors.initials: Y
authors.lastname: Shafeghati
authors.forename: Flemming
authors.initials: F
authors.lastname: Skovby
authors.forename: Seiji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Margo
authors.initials: M
authors.lastname: Whiteford
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D000199:Actins / Q000378:metabolism*; D001665:Binding Sites; D003285:Contractile Proteins / Q000235:genetics* / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics; D019066:Facies; D064448:Filamins; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D009139:Musculoskeletal Abnormalities / Q000235:genetics*; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D012720:Severity of Illness Index
chemical_list: D000199:Actins; D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins