Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathyReport as inadecuate




Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy - Download this document for free, or read online. Document in PDF available to download.

Journal of Muscle Research and Cell Motility

, Volume 37, Issue 3, pp 101–115

First Online: 21 July 2016Received: 18 May 2016Accepted: 09 July 2016DOI: 10.1007-s10974-016-9451-7

Cite this article as: D’Avila, F., Meregalli, M., Lupoli, S. et al. J Muscle Res Cell Motil 2016 37: 101. doi:10.1007-s10974-016-9451-7

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.

KeywordsMyofibrillar myopathies Exome sequencing LIM proteins BAG3 D’Avila F. and Meregalli M. are joint first Authors.

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Author: Francesca D’Avila - Mirella Meregalli - Sara Lupoli - Matteo Barcella - Alessandro Orro - Francesca De Santis - Clementin

Source: https://link.springer.com/







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