Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy.
Nat Med
; 15(11): 1281-8, 2009 Nov.
Article
en En
| MEDLINE
| ID: mdl-19881492
ABSTRACT
Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sarcómeros
/
Cardiomiopatía Dilatada
/
Predisposición Genética a la Enfermedad
/
Miocitos Cardíacos
/
Proteínas de Microfilamentos
/
Mutación
Tipo de estudio:
Etiology_studies
Límite:
Adult
/
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Alemania