Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.
OBJECTIVE
Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing.


BACKGROUND
Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation.


METHODS
We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain.


RESULTS
We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells.


CONCLUSIONS
Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM.
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Enkhsaikhan
E
Purevjav
Jaquelin
J
Varela
Micaela
M
Morgado
Debra L
DL
Kearney
Hua
H
Li
Michael D
MD
Taylor
Takuro
T
Arimura
Carole L
CL
Moncman
William
W
McKenna
Ross T
RT
Murphy
Siegfried
S
Labeit
Matteo
M
Vatta
Neil E
NE
Bowles
Akinori
A
Kimura
Aladin M
AM
Boriek
Jeffrey A
JA
Towbin
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D004695:Endocardial Fibroelastosis / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D060588:LIM Domain Proteins; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D060588:LIM Domain Proteins; C486890:NEBL protein, human