Nebulette knockout XXXX have normal cardiac function, but show Z-line widening and up-regulation of cardiac stress markers.

@entity1 @entity25325 @entity11459 @entity19 @entity384 @entity299 @entity71853
AIMS: Nebulette is a 109 kDa modular protein localized in the sarcomeric Z-line of the heart. In vitro studies have suggested a role of nebulette in stabilizing the thin filament, and missense mutations in the nebulette gene were recently shown to be causative for @entity384 and @entity11459 in @entity1 and @entity19 . However, the role of nebulette in vivo has remained elusive. To provide insights into the function of nebulette in vivo, we generated and studied nebulette-deficient ( @entity71853 (-) (/-)) @entity19 . METHODS AND RESULTS: @entity71853 (-) (/-) @entity19 were generated by replacement of exon 1 by Cre under the control of the endogenous nebulette promoter, allowing for lineage analysis using the @entity25325 Cre reporter strain. This revealed specific expression of nebulette in the heart, consistent with in situ hybridization results. @entity71853 (-) (/-) @entity19 exhibited normal cardiac function both under basal conditions and in response to transaortic constriction as assessed by echocardiography and haemodynamic analyses. Furthermore, histological, IF, and western blot analysis showed no @entity299 in @entity71853 (-) (/-) @entity19 up to 8 months of age. In contrast, transmission electron microscopy showed Z-line widening starting from 5 months of age, suggesting that nebulette is important for the integrity of the Z-line. Furthermore, up-regulation of cardiac stress responsive genes suggests the presence of chronic cardiac stress in @entity71853 (-) (/-) @entity19 . CONCLUSION: Nebulette is dispensable for normal cardiac function, although Z-line widening and up-regulation of cardiac stress markers were found in @entity71853 (-) (/-) heart. These results suggest that the nebulette disease causing mutations have dominant gain-of-function effects.
