Dominant cataract formation in association with a vimentin assembly disrupting mutation.
Cataracts are characterized by an opacification of the eye lens, often caused by protein misfolding and aggregation. The intermediate filament protein vimentin, which is highly expressed in lens fiber cells and in mesenchymal tissues, is a main structural determinant in these cells forming a membrane-connected cytoskeleton. Additional functions of vimentin remain to be identified. Here, we demonstrate that a mutation in VIM causes a dominant, pulverulent cataract. We sequenced the complete human VIM gene in 90 individuals suffering from congenital cataract and found a G596A change in exon 1 in a single individual, causing the missense mutation E151K in coil 1B of vimentin. The mutant vimentin formed an aberrant vimentin cytoskeleton and increased the proteasome activity in transfected cells. Furthermore, this mutation causes a severe kinetic defect in vimentin assembly both in vitro and in vivo. Hence, in conjunction with available mouse and cell culture models, our results reveal for the first time an important functional role for vimentin in the maintenance of lens integrity. Finally, this invites novel therapy approaches for cataracts.
Müller
Martin
M
Institut für Biochemie und Molekularbiologie, Abteilung für Zellbiochemie und LIMES, Universität Bonn, Bonn, Germany.
Bhattacharya
Shomi S
SS
Moore
Tony
T
Prescott
Quincy
Q
Wedig
Tatjana
T
Herrmann
Harald
H
Magin
Thomas M
TM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002386:Cataract / Q000151:congenital / Q000235:genetics*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006801:Humans; D007382:Intermediate Filaments / Q000648:ultrastructure; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014162:Transfection; D014746:Vimentin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D014746:Vimentin; D046988:Proteasome Endopeptidase Complex