Functional characterization of the novel DES mutation XXXX associated with @entity384 reveals a dominant filament assembly defect.

@entity1 @entity70797 @entity2283 @entity384 @entity70796
BACKGROUND: @entity384 ( @entity384 ) could be caused by mutations in more than 40 different genes. However, the pathogenic impact of specific mutations is in most cases unknown complicating the genetic counseling of affected families. Therefore, functional studies could contribute to distinguish pathogenic mutations and benign variants. Here, we present a novel heterozygous DES missense variant ( @entity70796 ; @entity70797 ) identified by next generation sequencing in a @entity384 @entity1 . DES encodes the cardiac intermediate filament protein @entity2283 , which has important functions in mechanical stabilization and linkage of the cell structures in cardiomyocytes. METHODS AND RESULTS: Cell transfection experiments and assembly assays of recombinant @entity2283 in combination with atomic force microscopy were used to investigate the impact of this novel DES variant on filament formation. @entity2283 - @entity70797 forms cytoplasmic aggregates indicating a severe intrinsic filament assembly defect of this mutant. Co-transfection experiments of wild-type and mutant @entity2283 conjugated to different fluorescence proteins revealed a dominant affect of this mutant on filament assembly. These experiments were complemented by apertureless scanning near-field optical microscopy. CONCLUSION: In vitro analysis demonstrated that @entity2283 - @entity70797 is unable to form regular filaments and accumulate instead within the cytoplasm. Therefore, we classified DES- @entity70797 as a likely pathogenic mutation. In conclusion, the functional characterization of DES- @entity70797 might have relevance for the genetic counseling of affected families with similar DES mutations and could contribute to distinguish pathogenic mutations from benign rare variants.
