Disease-associated Mutations in the Actin-Binding Domain of Filamin B Cause Cytoplasmic Focal Accumulations Correlating With Disease Severity

Hum Mutat. 2012 Apr;33(4):665-73. doi: 10.1002/humu.22012. Epub 2012 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Binding Sites
  • Contractile Proteins / genetics*
  • Contractile Proteins / metabolism*
  • Cytoplasm / metabolism*
  • Dwarfism / genetics
  • Facies
  • Filamins
  • Humans
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism*
  • Musculoskeletal Abnormalities / genetics*
  • Mutation*
  • Osteochondrodysplasias / genetics*
  • Repetitive Sequences, Nucleic Acid
  • Severity of Illness Index

Substances

  • Actins
  • Contractile Proteins
  • FLNB protein, human
  • Filamins
  • Microfilament Proteins

Supplementary concepts

  • Boomerang dysplasia