Alternative titles; symbols
HGNC Approved Gene Symbol: BAG3
Cytogenetic location: 10q26.11 Genomic coordinates (GRCh38) : 10:119,651,380-119,677,819 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.11 | ?Neuronopathy, distal hereditary motor, autosomal dominant 15 | 621094 | Autosomal dominant | 3 |
| Cardiomyopathy, dilated, 1HH | 613881 | Autosomal dominant | 3 | |
| Charcot-Marie-Tooth disease, axonal, type 2JJ | 621095 | Autosomal dominant | 3 | |
| Myopathy, myofibrillar, 6 | 612954 | Autosomal dominant | 3 |
The BAG3 gene encodes a member of the chaperone-assisted selective autophagy (CASA) complex, a large complex that identifies misfolded proteins and transfers them to ATP-dependent chaperones such as the Hsp70 family (see 140550) for refolding or directs them toward ubiquitination and proteasomal degradation. BAG3 binds to HSPB8 (608014) and other proteins in the CASA complex (summary by Adriaenssens et al., 2020).
Members of the BAG family, including BAG3, are cytoprotective proteins that bind to and regulate Hsp70 family molecular chaperones (Takayama et al., 1999; Homma et al., 2006).
Takayama et al. (1999) identified cDNAs corresponding to BAG3 and 3 other BAG1 (601497)-like proteins. The partial BAG3 cDNA encodes a protein containing a WW domain in the N-terminal region and a BAG domain in the C-terminal region. Selcen et al. (2009) noted that BAG3 also contains a C-terminal proline-rich domain that interacts with WW-domain proteins implicated in signal transduction and with SH3-domain proteins.
By database analysis using BAG4 (603884) as query, Jiang et al. (1999) identified BAG3, which has 61% identity to the C-terminal region of BAG4.
Using Western blot analysis, Pagliuca et al. (2003) found that BAG3 has an apparent molecular mass of 84 kD.
BAG3 is highly expressed in cardiomyocytes and skeletal muscle cells (summary by Adriaenssens et al., 2020).
Selcen et al. (2009) stated that the BAG3 gene contains 4 exons.
Gross (2015) mapped the BAG3 gene to chromosome 10q26.11 based on an alignment of the BAG3 sequence (GenBank AF071218) with the genomic sequence (GRCh38).
Takayama et al. (1999) demonstrated that BAG1, BAG2 (603882), and BAG3 bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a HIP (ST13; 606796)-repressible manner. These authors concluded that interactions with various BAG family proteins allow opportunities for specification and diversification of Hsp70/Hsc70 (HSPA8; 600816) chaperone functions.
Using in situ hybridization and immunohistochemical analyses, Liao et al. (2001) detected high BAG3 mRNA and protein expression in the cytoplasm of pancreatic tumor tissue, with little or no expression in adjacent normal pancreatic tissue. BAG3 was not overexpressed in other gastrointestinal cancers. Liao et al. (2001) hypothesized that the antiapoptotic function of BAG3 may contribute to the aggressiveness of pancreatic cancers.
Using Northern and Western blot analyses, Pagliuca et al. (2003) found that expression of BAG3, together with that of HSP70 and metallothionein (see MT1A; 156350), was upregulated in HeLa cells exposed to heat or to the heavy metals zinc and cadmium. During heat and metal stress, the intracellular localization of BAG3 changed from a homogeneous cytoplasmic distribution to a reticular perinuclear distribution, where BAG3 colocalized with a rough endoplasmic reticulum (ER) marker. Pagliuca et al. (2003) noted that the ER is the major organelle in the integration of damage-sensing and proapoptotic stimuli and hypothesized that BAG3 may have a role in the cellular response to environmental stress.
In skeletal muscle, BAG3 plays a role in cell resilience to mechanical stress through chaperone-associated selected autophagy (CASA), which removes misfolded proteins. Similarly, peripheral nerves are subject to mechanical tension and prone to protein misfolding or aggregation. BAG3 binds to HSPB8 (608014) via 2 conserved Ile-Pro-Val (IPV) motifs. This interaction is essential for function of the CASA complex (summary by Shy et al., 2018).
Myofibrillar Myopathy 6
In 3 unrelated patients with childhood-onset of rapidly progressive myofibrillar myopathy (MFM6; 612954), Selcen et al. (2009) identified the same heterozygous mutation in the BAG3 gene (P209L; 603883.0001). The unaffected parents of 2 patients did not carry the mutation, indicating de novo occurrence; DNA was not available from the unaffected parents of the third patient.
Lee et al. (2012) identified a de novo heterozygous P209L mutation in a Chinese girl with myofibrillar myopathy. The patient and her father had an R258W missense mutation (603883.0009) in the BAG3 gene. The father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual.
In a man with adult-onset myofibrillar myopathy, Semmler et al. (2014) identified a de novo heterozygous missense mutation in the BAG3 gene (P209Q; 603883.0010).
In a 15-year-old Korean girl with MFM6 and a peripheral axonal sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Kim et al. (2018) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.
In a 13-year-old Caucasian girl with MFM6 and a peripheral sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Malatesta et al. (2020) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by trio-based exome sequencing; functional studies of the variant were not performed.
In a Japanese man and his mother with MFM6 and an axonal sensorimotor peripheral neuropathy consistent with Charcot-Marie-Tooth disease, Hamaguchi et al. (2020) identified a heterozygous missense mutation in the BAG3 gene (P470S; 603883.0012). The mutation was found by sequencing a MFM-targeted gene panel and confirmed by Sanger sequencing. No other family members were sequenced. Functional studies of the variant were not performed.
Charcot-Marie-Tooth Disease Type 2JJ
In 9 affected individuals from 2 large multigenerational families with axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ; 621095), Shy et al. (2018) identified a heterozygous P209S mutation in the BAG3 gene (603883.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The P209S variant occurs at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8. Functional studies of the variant were not performed, buy Shy et al. (2018) suggested that disruption of the IPV motif could interrupt BAG3-HSPB8 binding and fail to promote clearance of aggregate proteins in peripheral nerves, resulting in damage to the nerves. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed.
In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, Fu et al. (2020) identified a heterozygous P209S mutation in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
Autosomal Dominant Distal Hereditary Motor Neuronopathy 15
In 8 affected members of a Spanish family with autosomal dominant distal hereditary motor neuronopathy-15 (HMND15; 621094), de Fuenmayor-Fernandez de la Hoz et al. (2024) identified a heterozygous frameshift in the BAG3 gene (Val505GlyfsTer6; 603883.0013), thus eliminating the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein. Functional studies of the variant were not performed, but the authors noted that mutant caspase-resistant BAG3 cells are able to resist apoptosis in vitro. They suggested that the frameshift mutation in this family, eliminating the LEAD sequence, would decrease apoptosis and result in increased expression of mutant BAG3, possibly causing increased binding to HSPB8 (608014), the formation of intracellular aggregates, and disrupted autophagy in lower motor neurons. The patients had no sensory abnormalities. Sural nerve biopsy was not performed; muscle biopsy showed neurogenic changes, but was otherwise normal.
Dilated Cardiomyopathy 1HH
In a large 3-generation family segregating autosomal dominant dilated cardiomyopathy (CMD1HH; 613881), Norton et al. (2011) performed whole-exome sequencing and genomewide analysis of copy number variation and identified an 8,733-bp deletion in the BAG3 gene (603883.0002) that was present in all 7 affected family members and absent from 355 controls. Norton et al. (2011) then sequenced exons 2, 3, and 4 of BAG3 in an additional 311 CMD probands who were negative for mutation in 15 known CMD-associated genes, and identified heterozygous point mutations in 7 unrelated probands that were not found in 2,644 control chromosomes (see, e.g., 603883.0003-603883.0006). Knockdown of bag3 in a zebrafish model recapitulated CMD and heart failure.
In 72 Japanese probands with familial CMD, Arimura et al. (2011) analyzed the BAG3 gene and identified heterozygosity for 2 missense mutations in 2 probands: R218W (603883.0007) and L462P (603883.0008).
In transfected neonatal rat cardiomyocytes (NRCs), Arimura et al. (2011) demonstrated that the CMD-associated mutations R218W and L462P disturbed the assembly and integrity of Z-discs as well as the nuclear localization of BAG3 protein, whereas such abnormalities were not observed with the P209L myofibrillar myopathy (MFM) mutation. In addition, analysis of transfected C2C12 myoblast cells showed that myotube formation was disturbed by the MFM mutation but not by the CMD mutations. TUNEL assay in NRCs and quantified apoptosis of H9c2 cells also indicated that the CMD-associated mutations R218W and L462P increased susceptibility to stress-induced apoptosis compared to wildtype, whereas the P209L MFM mutation did not.
In adult mice, Homma et al. (2006) showed that Bag3 is prominently expressed in striated and cardiac muscle and colocalized with Z-discs, with lesser expression in other tissues. Mice with homozygous disruption of the Bag3 gene developed normally, but deteriorated postnatally with stunted growth evident by 1 to 2 weeks of age, and death by 4 weeks. Bag3-deficient mice developed a fulminant myopathy characterized by noninflammatory myofibrillar degeneration with apoptotic features. Cardiac muscle was also affected. Knockdown of Bag3 expression in cultured myoblasts increased apoptosis on induction of differentiation, suggesting that Bag3 is needed for maintenance of myotube survival and confirming a cell autonomous role for Bag3 in muscle. Homma et al. (2006) concluded that, although BAG3 is not required for muscle development, it appears to be critically important for maintenance of mature skeletal muscle.
In 3 unrelated patients with late-childhood onset of autosomal dominant myofibrillar myopathy-6 (MFM6; 612954), Selcen et al. (2009) identified a heterozygous 626C-T transition in exon 3 of the BAG3, gene, resulting in a pro209-to-leu (P209L) substitution. The mutation was not present in 200 control individuals. The unaffected parents of 2 patients did not carry the mutation, indicating de novo occurrence; DNA was not available from the unaffected parents of the third patient. Patients showed a rapidly progressive myopathy affecting both skeletal and cardiac muscle with severe respiratory insufficiency. In vitro functional expression studies showed that the mutant protein tended to aggregate into small granules, suggesting altered folding.
Lee et al. (2012) identified a de novo heterozygous P209L mutation in a Chinese girl with onset of myofibrillar myopathy at age 6 years. She had slowly progressive muscle weakness, clumsy walking, rapidly progressive contractures of the Achilles tendons, limited spinal movement, mildly restrictive lung disease, hypertrophic cardiomyopathy, prolonged QT interval, and decreased motor nerve conduction velocities, suggesting a neurogenic axonal disease. Electron microscopy of muscle biopsy showed sarcoplasmic accumulations of electron-dense granulofilamentous material and myofibrillar degeneration with minicores. The patient and her father had an R258W missense mutation (603883.0009) in the BAG3 gene. Her father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual.
In 4 patients from 3 unrelated families with MFM6, Odgerel et al. (2010) identified a heterozygous P209L mutation. The mutation occurred de novo in 2 patients. Two brothers inherited the mutation from their unaffected father, who was somatic mosaic for the mutation, with an expression level of 17% in the peripheral blood lymphocytes.
In 4 patients with MFM6, Jaffer et al. (2012) identified a heterozygous P209L mutation. One of the patients had a sister who was similarly affected, but DNA was not available. Their father had died of a similar but milder disorder at age 30 years, suggesting that he may have been somatic mosaic for the mutation.
In a 15-year-old Korean girl with MFM6 and a peripheral axonal sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Kim et al. (2018) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.
In a 13-year-old Caucasian girl with MFM6 and a peripheral sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Malatesta et al. (2020) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by trio-based exome sequencing; functional studies of the variant were not performed.
In 7 affected members of a large 3-generation family segregating autosomal dominant dilated cardiomyopathy (CMD1HH; 613881), Norton et al. (2011) identified heterozygosity for an 8,733-bp deletion encompassing exon 4 of the BAG3 gene. The mutation, which was also present in 3 unaffected family members, was not found in 355 controls. Two affected individuals died of advanced heart failure at age 38 years and age 44 years, and another underwent heart transplant at age 23 years.
In a mother and son who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 59 years and 41 years, respectively, Norton et al. (2011) identified heterozygosity for a c.211C-T transition (c.211C-T, NM_004281.3) in exon 2 of the BAG3 gene, resulting in an arg71-to-trp (R71W) substitution. The mutation was not found in 2,644 control chromosomes. The mother underwent heart transplant at age 65 years.
In a brother and sister who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 25 years and 34 years, respectively, Norton et al. (2011) identified heterozygosity for a c.367C-T transition (c.367C-T, NM_004281.3) in exon 2 of the BAG3 gene, resulting in an arg123-to-ter (R123X) substitution. The mutation was present in their father, who had undergone a heart transplant for an unknown type of cardiomyopathy at 40 years of age, and was also present in an asymptomatic sister, but was not found in 2,644 control chromosomes. The brother had undergone heart transplant at 26 years of age, but his affected sister had only mild left ventricular dysfunction.
In a man who was diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at 47 years of age and died at age 54 years, Norton et al. (2011) identified heterozygosity for a 1-bp deletion (c.652delC, NM_004281.3) in exon 3 of the BAG3 gene, resulting in a frameshift predicted to cause a premature termination codon. The mutation was not found in 2,644 control chromosomes.
In a man who was diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at 50 years of age and underwent heart transplant within a year, Norton et al. (2011) identified heterozygosity for a c.1430G-A transition (c.1430G-A, NM_004281.3) in exon 4 of the BAG3 gene, resulting in an arg477-to-his (R477H) substitution. The mutation was not found in 2,644 control chromosomes. The proband's affected father was deceased, but the mutation was detected in his paternal uncle, who was diagnosed with CMD at 47 years of age and underwent heart transplant at age 57 years.
In a 76-year-old Japanese man who developed dilated cardiomyopathy at age 73 years (CMD1HH; 613881), Arimura et al. (2011) identified heterozygosity for a c.652C-T transition (c.652C-T, NM_004281.3) in exon 3 of the BAG3 gene, resulting in an arg218-to-trp (R218W) substitution at a highly conserved residue. The patient had 3 affected sisters, 2 of whom had died suddenly; neither of their deceased parents was known to be affected. DNA was not analyzed from any of these family members. Transfection studies in neonatal rat cardiomyocytes (NRCs) demonstrated that wildtype BAG3 had a striated pattern of assembly and colocalized with the Z-disc markers alpha-actinin (see 102575) and desmin (125660), whereas the R218W mutant did not show a striated pattern, and Z-disc assembly as represented by localization of alpha-actinin and desmin was impaired. TUNEL assay in NRCs and quantification of apoptosis in H9c2 cells both indicated that the R218W mutant increased susceptibility to stress-induced apoptosis compared to wildtype.
In a 41-year-old Japanese woman who developed dilated cardiomyopathy at age 34 years (CMD1HH; 613881), Arimura et al. (2011) identified heterozygosity for a c.1385T-C transition (c.1385T-C, NM_004281.3) in exon 4 of the BAG3 gene, resulting in a leu462-to-pro (L462P) substitution at a highly conserved residue. The mutation was also detected in the proband's 27-year-old sister, who did not have overt CMD but showed slight systolic dysfunction, with regional hypokinesia in the posterior ventricular wall. However, the mutation was not found in their unaffected father or brother or in 400 Japanese controls. Their affected mother had died suddenly at age 52 years. Electrocardiographic analysis of the 2 affected individuals showed no primary conduction defect, serum creatine kinase levels were not elevated, and neither showed signs of skeletal myopathy or neuropathy. Transfection studies in neonatal rat cardiomyocytes demonstrated that wildtype BAG3 had a striated pattern of assembly and colocalized with the Z-disc markers alpha-actinin (see 102575) and desmin (125660), whereas the L462P mutant did not show a striated pattern, and Z-disc assembly as represented by localization of alpha-actinin and desmin was impaired. TUNEL assay in NRCs and quantification of apoptosis in H9c2 cells both indicated that the L462P mutant increased susceptibility to stress-induced apoptosis compared to wildtype.
This variant is classified as a variant of unknown significance because its contribution to cardiac or muscle disease has not been confirmed.
Lee et al. (2012) identified a heterozygous c.772C-T transition (c.772C-T, NM_004281.3) in the BAG3 gene, resulting in an arg258-to-trp (R258W) substitution at a highly conserved residue in a Chinese father and daughter with prolonged QT interval. The variant was found in 2 of 286 control chromosomes (allele frequency of 0.007). Functional studies were not performed. The variant was identified by study of the daughter, who had myofibrillar myopathy (MFM6; 612954) caused by a de novo heterozygous known pathogenic mutation in the BAG3 gene (P209L; 603883.0001). The father had no abnormal neuromuscular findings, and his prolonged QT interval was asymptomatic. It was unclear whether the R258W variant contributed to the phenotype in either individual.
In a man with adult-onset myofibrillar myopathy-6 (MFM6; 612954), Semmler et al. (2014) identified a de novo heterozygous c.626C-A transversion (c.626C-A, NM_004281.3) in exon 3 of the BAG3 gene, resulting in a pro209-to-gln (P209Q) substitution. The mutation was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in either unaffected parent. Functional studies of the variant were not performed, but a different mutation at this codon (P209L; 603883.0001) has been found in multiple patients with MFM6. The patient developed distal lower limb weakness at age 34 years, which progressed to proximal muscle weakness affecting the upper and lower limbs. Muscle biopsy showed vacuoles, core-like lesions, and some necrotic fibers; ultrastructural examination showed tubulofilamentous accumulations, Z-disc streaming, and the accumulation of granulofilamentous material. He also had an axonal sensorimotor polyneuropathy manifest as decreased vibration sense and ataxic gait, but sural nerve biopsy did not show giant axons. He did not have cardiac or respiratory muscle involvement, indicating a relatively mild phenotype.
In 9 affected individuals from 2 large multigenerational families with axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ; 621095), Shy et al. (2018) identified a heterozygous c.625C-T transition in exon 3 of the BAG3 gene, resulting in a pro209-to-ser (P209S) substitution at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8 (608014). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed.
In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, Fu et al. (2020) identified a heterozygous P209S mutation (c.625C-T, NM_004281) in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
In a Japanese man and his mother with adult-onset myofibrillar myopathy-6 (MFM6; 612954) and an axonal sensorimotor peripheral neuropathy consistent with Charcot-Marie-Tooth disease, Hamaguchi et al. (2020) identified a heterozygous c.1408C-T transition (c.1408C-T, NM_004281.3) in the BAG3 gene, resulting in a pro470-to-ser (P470S) substitution. The mutation was found by sequencing a MFM-targeted gene panel and confirmed by Sanger sequencing. No other family members were sequenced. Functional studies of the variant were not performed.
In 8 affected members of a Spanish family with autosomal dominant distal hereditary motor neuronopathy-15 (HMND15; 621094), de Fuenmayor-Fernandez de la Hoz et al. (2024) identified a heterozygous 4-bp insertion (c.1513_1514insGGAC, NM_004281.3) in the BAG3 gene, predicted to result in a frameshift and premature termination (Val505GlyfsTer6) that would eliminate the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein.
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