Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.
J Muscle Res Cell Motil
; 37(3): 101-15, 2016 06.
Article
en En
| MEDLINE
| ID: mdl-27443559
ABSTRACT
Myofibrillar myopathies (MFMs) are genetically heterogeneous dystrophies characterized by the disintegration of Z-disks and myofibrils and are associated with mutations in genes encoding Z-disk or Z-disk-related proteins. The c.626 C > T (p.P209L) mutation in the BAG3 gene has been described as causative of a subtype of MFM. We report a sporadic case of a 26-year-old Italian woman, affected by MFM with axonal neuropathy, cardiomyopathy, rigid spine, who carries the c.626 C > T mutation in the BAG3 gene. The patient and her non-consanguineous healthy parents and brother were studied with whole exome sequencing (WES) to further investigate the genetic basis of this complex phenotype. In the patient, we found that the BAG3 mutation is associated with variants in the NRAP and FHL1 genes that encode muscle-specific, LIM domain containing proteins. Quantitative real time PCR, immunohistochemistry and Western blot analysis of the patient's muscular biopsy showed the absence of NRAP expression and FHL1 accumulation in aggregates in the affected skeletal muscle tissue. Molecular dynamic analysis of the mutated FHL1 domain showed a modification in its surface charge, which could affect its capability to bind its target proteins. To our knowledge this is the first study reporting, in a BAG3 MFM, the simultaneous presence of genetic variants in the BAG3 and FHL1 genes (previously described as independently associated with MFMs) and linking the NRAP gene to MFM for the first time.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Miopatías Estructurales Congénitas
/
Péptidos y Proteínas de Señalización Intracelular
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Proteínas Adaptadoras Transductoras de Señales
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Proteínas Reguladoras de la Apoptosis
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Proteínas con Dominio LIM
/
Proteínas Musculares
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Female
/
Humans
País/Región como asunto:
Europa
Idioma:
En
Revista:
J Muscle Res Cell Motil
Año:
2016
Tipo del documento:
Article
País de afiliación:
Italia