title: Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.
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.
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Rudinì 8, 20100, Milan, Italy.|Filarete Foundation, Viale Ortles, 22, 20100, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Avila
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via F. Sforza, 35, 20122, Milan, Italy.|YStem s.r.l., viale Piave 21, 20129, Milan, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Meregalli
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Rudinì 8, 20100, Milan, Italy.|Filarete Foundation, Viale Ortles, 22, 20100, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lupoli
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Rudinì 8, 20100, Milan, Italy.|Filarete Foundation, Viale Ortles, 22, 20100, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Barcella
authors.affiliation: Institute for Biomedical Technologies, CNR, Via Fratelli Cervi N. 93, Segrate, 20090, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orro
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via F. Sforza, 35, 20122, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Santis
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via F. Sforza, 35, 20122, Milan, Italy.
authors.forename: Clementina
authors.initials: C
authors.lastname: Sitzia
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via F. Sforza, 35, 20122, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Farini
authors.affiliation: Institute for Biomedical Technologies, CNR, Via Fratelli Cervi N. 93, Segrate, 20090, Milan, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: D'Ursi
authors.affiliation: YStem s.r.l., viale Piave 21, 20129, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Erratico
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza per lo studio delle malattie neurodegenerative (CEND), Università degli studi di Milano, via Balzaretti, 9, 20100, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cristofani
authors.affiliation: Institute for Biomedical Technologies, CNR, Via Fratelli Cervi N. 93, Segrate, 20090, Milan, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Rudinì 8, 20100, Milan, Italy.|Filarete Foundation, Viale Ortles, 22, 20100, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Braga
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Rudinì 8, 20100, Milan, Italy.|Filarete Foundation, Viale Ortles, 22, 20100, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza per lo studio delle malattie neurodegenerative (CEND), Università degli studi di Milano, via Balzaretti, 9, 20100, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Rudinì 8, 20100, Milan, Italy. cristina.barlassina@unimi.it.|Filarete Foundation, Viale Ortles, 22, 20100, Milan, Italy. cristina.barlassina@unimi.it.|Department of Health Sciences, Università degli Studi di Milano, c/o Filarete Foundation, Viale Ortles 22/4, 20139, Milan, Italy. cristina.barlassina@unimi.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via F. Sforza, 35, 20122, Milan, Italy. yvan.torrente@unimi.it.|YStem s.r.l., viale Piave 21, 20129, Milan, Italy. yvan.torrente@unimi.it.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy; D060588:LIM Domain Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C108533:NRAP protein, human
keywords: BAG3; Exome sequencing; LIM proteins; Myofibrillar myopathies