A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy

Hamaguchi, Mai; Kokubun, Norito; Inoue, Michio; Komagamine, Tomoko; Aoki, Reika; Nishino, Ichizo; Hirata, Koichi

doi:10.1016/j.nmd.2020.07.012

Cited by 3 publications

(3 citation statements)

References 22 publications

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“… 31 The importance of IPV in cardiomyopathies has been highlighted by disease‐causing (classified as pathogenic/likely pathogenic [P/LP]) point mutations at the Pro209 position in the second IPV motif of BAG3. 32 The mutant protein of the toxic gain‐of‐function mutation p.Pro209Leu in BAG3 forms aggregates with the wild‐type protein and causes BAG3 insufficiency. 33 The proline‐rich repeat (PXXP) region binds to SH3 (Src homology 3) motifs and mediates protein–protein interaction, eg, with phospholipase C‐γ.…”

Section: Bag3 Genementioning

confidence: 99%

“…All 6 P/LP variants are located in a functional domain, ie, the amino acid 209 position at the second IPV domain, and amino acid positions at the BAG domain. 29 , 32 , 86 Interestingly, the missense variant p.Pro209Leu was initially identified as having an association with myofibrillar myopathy and restrictive cardiomyopathy or hypertrophic cardiomyopathy, 86 , 87 , 88 while later studies also reported the phenotype of DCM in relation with p.Pro209Leu. 32 , 88 In Zebrafish models, p.Pro209Leu was demonstrated as a toxic gain‐of‐function mutation.…”

Section: Rare Mutations and Phenotypic Effectsmentioning

confidence: 99%

“… 29 , 32 , 86 Interestingly, the missense variant p.Pro209Leu was initially identified as having an association with myofibrillar myopathy and restrictive cardiomyopathy or hypertrophic cardiomyopathy, 86 , 87 , 88 while later studies also reported the phenotype of DCM in relation with p.Pro209Leu. 32 , 88 In Zebrafish models, p.Pro209Leu was demonstrated as a toxic gain‐of‐function mutation. 33 Loss of BAG3 may result in myofibrillar disintegration, while the mutant protein of p.Pro209Leu can rescue the myofibrillar disintegration phenotype.…”

Section: Rare Mutations and Phenotypic Effectsmentioning

confidence: 99%

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Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies

Feldman

Hákonarson

2022

JAHA

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Nonischemic dilated cardiomyopathy is a common form of heart muscle disease in which genetic factors play a critical etiological role. In this regard, both rare disease‐causing mutations and common disease‐susceptible variants, in the Bcl‐2–associated athanogene 3 ( BAG3 ) gene have been reported, highlighting the critical role of BAG3 in cardiomyocytes and in the development of dilated cardiomyopathy. The phenotypic effects of the BAG3 mutations help investigators understand the structure and function of the BAG3 gene. Indeed, we report herein that all of the known pathogenic/likely pathogenic variants affect at least 1 of 3 protein functional domains, ie, the WW domain, the second IPV (Ile‐Pro‐Val) domain, or the BAG domain, whereas none of the missense nontruncating pathogenic/likely pathogenic variants affect the proline‐rich repeat (PXXP) domain. A common variant, p.Cys151Arg, associated with reduced susceptibility to dilated cardiomyopathy demonstrated a significant difference in allele frequencies among diverse human populations, suggesting evolutionary selective pressure. As BAG3 ‐related therapies for heart failure move from the laboratory to the clinic, the ability to provide precision medicine will depend in large part on having a thorough understanding of the potential effects of both common and uncommon genetic variants on these target proteins. The current review article provides a roadmap that investigators can utilize to determine the potential interactions between a patient's genotype, their phenotype, and their response to therapeutic interventions with both gene delivery and small molecules.

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Section: Bag3 Genementioning

confidence: 99%

Section: Rare Mutations and Phenotypic Effectsmentioning

confidence: 99%

Section: Rare Mutations and Phenotypic Effectsmentioning

confidence: 99%

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Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies

Feldman

Hákonarson

2022

JAHA

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The chaperone-assisted selective autophagy complex dynamics and dysfunctions

et al. 2023

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Each protein must be synthesized with the correct amino acid sequence, folded into its native structure, and transported to a relevant subcellular location and protein complex. If any of these steps fail, the cell has the capacity to break down aberrant proteins to maintain protein homeostasis (also called proteostasis). All cells possess a set of well-characterized protein quality control systems to minimize protein misfolding and the damage it might cause. Autophagy, a conserved pathway for the degradation of long-lived proteins, aggregates, and damaged organelles, was initially characterized as a bulk degradation pathway. However, it is now clear that autophagy also contributes to intracellular homeostasis by selectively degrading cargo material. One of the pathways involved in the selective removal of damaged and misfolded proteins is chaperone-assisted selective autophagy (CASA). The CASA complex is composed of three main proteins (HSPA, HSPB8 and BAG3), essential to maintain protein homeostasis in muscle and neuronal cells. A failure in the CASA complex, caused by mutations in the respective coding genes, can lead to (cardio)myopathies and neurodegenerative diseases. Here, we summarize our current understanding of the CASA complex and its dynamics. We also briefly discuss how CASA complex proteins are involved in disease and may represent an interesting therapeutic target. Abbreviation ALP: autophagy lysosomal pathway; ALS: amyotrophic lateral sclerosis; AMOTL1: angiomotin like 1; ARP2/3: actin related protein 2/3; BAG: BAG cochaperone; BAG3: BAG cochaperone 3; CASA: chaperone-assisted selective autophagy; CMA: chaperone-mediated autophagy; DNAJ/HSP40: DnaJ heat shock protein family (Hsp40); DRiPs: defective ribosomal products; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK1/HRI: eukaryotic translation initiation factor 2 alpha kinase 1; GABARAP: GABA type A receptor-associated protein; HDAC6: histone deacetylase 6; HSP: heat shock protein; HSPA/HSP70: heat shock protein family A (Hsp70); HSP90: heat shock protein 90; HSPB8: heat shock protein family B (small) member 8; IPV: isoleucine-proline-valine; ISR: integrated stress response; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LATS1: large tumor suppressor kinase 1; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOC: microtubule organizing center; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; NFE2L2: NFE2 like bZIP transcription factor 2; PLCG/PLCγ: phospholipase C gamma; polyQ: polyglutamine; PQC: protein quality control; PxxP: proline-rich; RAN translation: repeat-associated non-AUG translation; SG: stress granule; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; STK: serine/threonine kinase; SYNPO: synaptopodin; TBP: TATA-box binding protein; TARDBP/TDP-43: TAR DNA binding protein; TFEB: trans...

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