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

Francesca D’Avila, Mirella Meregalli, Sara Lupoli, Matteo Barcella, Alessandro Orro, Francesca de Santis, Clementina Sitzia, Andrea Farini, Pasqualina D’Ursi, Silvia Erratico, Riccardo Cristofani, Luciano Milanesi, Daniele Braga, Daniele Cusi, Angelo Poletti, Cristina Barlassina, Yvan Torrente

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)101-115
Number of pages15
JournalJournal of Muscle Research and Cell Motility
Volume37
Issue number3
DOIs
Publication statusPublished - 2016

Fingerprint

Exome
Gene encoding
Genes
Mutation
Proteins
Muscle
LIM Domain Proteins
Biopsy
Disintegration
Muscles
Surface charge
Myofibrils
Dynamic analysis
Molecular Dynamics Simulation
Molecular dynamics
Cardiomyopathies
Myofibrillar Myopathy
Siblings
Real-Time Polymerase Chain Reaction
Tissue

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 journalArticle

D’Avila, F, Meregalli, M, Lupoli, S, Barcella, M, Orro, A, de Santis, F, Sitzia, C, Farini, A, D’Ursi, P, Erratico, S, Cristofani, R, Milanesi, L, Braga, D, Cusi, D, Poletti, A, Barlassina, C & Torrente, Y 2016, 'Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy', Journal of Muscle Research and Cell Motility, vol. 37, no. 3, pp. 101-115. https://doi.org/10.1007/s10974-016-9451-7
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. / Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy. In: Journal of Muscle Research and Cell Motility. 2016 ; Vol. 37, No. 3. pp. 101-115.
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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.",
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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.

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KW - Exome sequencing

KW - LIM proteins

KW - Myofibrillar myopathies

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