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.
| Original language | English |
|---|---|
| Pages (from-to) | 101-115 |
| Number of pages | 15 |
| Journal | Journal of Muscle Research and Cell Motility |
| Volume | 37 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2016 |
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Keywords
- BAG3
- Exome sequencing
- LIM proteins
- Myofibrillar myopathies
ASJC Scopus subject areas
- Physiology
- Cell Biology
- Biochemistry
Cite this
Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy. / D’Avila, Francesca; Meregalli, Mirella; Lupoli, Sara; Barcella, Matteo; Orro, Alessandro; de Santis, Francesca; Sitzia, Clementina; Farini, Andrea; D’Ursi, Pasqualina; Erratico, Silvia; Cristofani, Riccardo; Milanesi, Luciano; Braga, Daniele; Cusi, Daniele; Poletti, Angelo; Barlassina, Cristina; Torrente, Yvan.
In: Journal of Muscle Research and Cell Motility, Vol. 37, No. 3, 2016, p. 101-115.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy
AU - D’Avila, Francesca
AU - Meregalli, Mirella
AU - Lupoli, Sara
AU - Barcella, Matteo
AU - Orro, Alessandro
AU - de Santis, Francesca
AU - Sitzia, Clementina
AU - Farini, Andrea
AU - D’Ursi, Pasqualina
AU - Erratico, Silvia
AU - Cristofani, Riccardo
AU - Milanesi, Luciano
AU - Braga, Daniele
AU - Cusi, Daniele
AU - Poletti, Angelo
AU - Barlassina, Cristina
AU - Torrente, Yvan
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - BAG3
KW - Exome sequencing
KW - LIM proteins
KW - Myofibrillar myopathies
UR - http://www.scopus.com/inward/record.url?scp=84979200841&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979200841&partnerID=8YFLogxK
U2 - 10.1007/s10974-016-9451-7
DO - 10.1007/s10974-016-9451-7
M3 - Article
AN - SCOPUS:84979200841
VL - 37
SP - 101
EP - 115
JO - Journal of Muscle Research and Cell Motility
JF - Journal of Muscle Research and Cell Motility
SN - 0142-4319
IS - 3
ER -