Mutation in BAG3 causes severe dominant childhood muscular dystrophy
Open accessAbstract
Objective: Myofibrillar myopathies (MFMs) are morphologically distinct but genetically heterogeneous muscular dystrophies in which disintegration of Z disks and then of myofibrils is followed by ectopic accumulation of multiple proteins. Cardiomyopathy, neuropathy, and dominant inheritance are frequent associated features. Mutations in αB‐crystallin, desmin, myotilin, Zasp, or filamin‐C can cause MFMs and were detected in 32 of 85 patients of the Mayo MFM cohort. Bag3, another Z‐disk–associated protein, has antiapoptotic properties, and its targeted deletion in mice causes fulminant myopathy with early lethality. We therefore searched for mutations in BAG3 in 53 unrelated MFM patients. Methods: We searched for mutations in BAG3 by direct sequencing. We analyzed structural changes in muscle by histochemistry, immunocytochemistry, and electron microscopy, examined mobility of the mutant Bag3 by nondenaturing electrophoresis, and searched for abnormal aggregation of the mutant protein in COS‐7 (SV‐40 transformed monkey kidney fibroblast‐7) cells. Results: We identified a heterozygous p.Pro209Leu mutation in three patients. All presented in childhood, had progressive limb and axial muscle weakness, and experienced development of cardiomyopathy and severe respiratory insufficiency in their teens; two had rigid spines, and one a peripheral neuropathy. Electron microscopy showed disintegration of Z disks, extensive accumulation of granular debris and larger inclusions, and apoptosis of 8% of the nuclei. On nondenaturing electrophoresis of muscle extracts, the Bag3 complex migrated faster in patient than control extracts, and expression of FLAG‐labeled mutant and wild‐type Bag3 in COS cells showed abnormal aggregation of the mutant protein. Interpretation: We conclude mutation in Bag3 defines a novel severe autosomal dominant childhood muscular dystrophy. Ann Neurol 2008
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Loss-of-function of Bag3 causes severe myopathy symptoms in mice and humans.
“The importance of Bag3 for skeletal muscle is further demonstrated by the finding that a loss-of-function of Bag3 causes severe myopathy symptoms in mice and humans (62, 117).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [117]
The Discussion reports that targeted Bag3 deletion causes severe myopathy in mice and that three patients with a BAG3 mutation had severe childhood-onset muscle weakness. It describes altered function of the human mutant protein as a prediction, however, and does not establish that the patients’ mutation causes loss of function. (LLM, conf=0.87)
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- Authors
- Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., & Engel, A. G.
- Affiliations
- Mayo Clinic (US)
- Lurie Children's Hospital (US)
- University of Padua (IT)
- Great Ormond Street Hospital (GB)
- Corresponding author
- Selcen, Duygu
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-01
- Volume
- 65
- Issue
- 1
- Pages
- 83-89
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2639628
- OpenAlex
- W2013006994
- Cited by
- 357
- References
- 33
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 16 · 2023: 19 · 2022: 12 · 2021: 29 · 2020: 23 · 2019: 18 · 2018: 29 · 2017: 31 · 2016: 28 · 2015: 24 · 2014: 23 · 2013: 23 · 2012: 21
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (K08NS050106, R01NS006277, R56NS006277, NS50106)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- BAG3, myofibrillar myopathy, childhood muscular dystrophy, autosomal dominant inheritance, cardiomyopathy, peripheral neuropathy, respiratory failure, protein aggregation, apoptosis
- MeSH terms
- Adolescent, Animals, Chlorocebus aethiops, Child, Crystallins, DNA Mutational Analysis, Female, Humans, Male, Muscle Proteins, Muscular Dystrophies, Mutation, Transfection, Muscle Fibers, Skeletal, COS Cells, In Situ Nick-End Labeling, Microscopy, Electron, Transmission, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins
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