title: BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome.
abstract: BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.
authors.affiliation: Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kostera-Pruszczyk
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Suszek
authors.affiliation: Department of Medical Genetics, Medical University of Warsaw, 3c Pawińskiego St., 02-106, Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Płoski
authors.affiliation: Laboratory of Molecular Biology, Institute of Cardiology, 42 Alpejska St., 04-628, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Franaszczyk
authors.affiliation: Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Potulska-Chromik
authors.affiliation: Department of Internal Medicine and Cardiology with the Center for Diagnosis and Treatment of Venous Thromboembolism, Medical University of Warsaw, 4 Lindleya St., 02-005, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Pruszczyk
authors.affiliation: Department of Pediatric Cardiology, Medical University of Lublin, Chodźki 2, 20-093, Lublin, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Sadurska
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093, Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Karolczak
authors.affiliation: Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097, Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kamińska
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093, Warsaw, Poland. j.redowicz@nencki.gov.pl.
authors.forename: Maria Jolanta
authors.initials: MJ
authors.lastname: Rędowicz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D011115:Polyneuropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human
keywords: BAG3; HSP70; Long Q-T syndrome myopathy; Sarcomere; Z-disc