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.
Purevjav
Enkhsaikhan
E
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Varela
Jaquelin
J
Morgado
Micaela
M
Kearney
Debra L
DL
Li
Hua
H
Taylor
Michael D
MD
Arimura
Takuro
T
Moncman
Carole L
CL
McKenna
William
W
Murphy
Ross T
RT
Labeit
Siegfried
S
Vatta
Matteo
M
Bowles
Neil E
NE
Kimura
Akinori
A
Boriek
Aladin M
AM
Towbin
Jeffrey A
JA
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