BAG3 – Dilated Cardiomyopathy

Autosomal‐dominant dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement, systolic dysfunction, and progression to heart failure (HF). In 2011, whole‐exome sequencing and genome‐wide copy number analysis in a multigenerational family with autosomal‐dominant DCM identified an 8.7 kb deletion spanning exon 4 of BAG3 in seven affected members but not in 355 controls (PMID:21353195).

Subsequent screening of 311 unrelated DCM probands revealed one frameshift, two nonsense, and four rare missense BAG3 variants absent in controls; four segregated with disease in distinct families, bringing the total to over 40 independent heterozygous variants (PMID:21353195). In a large Spanish pedigree, a novel frameshift (c.728_729del) present in 32 carriers showed 21 clinically affected relatives and 10 asymptomatic carriers, underscoring incomplete penetrance (PMID:27391596).

Inheritance is autosomal dominant. Segregation analysis across multiple pedigrees documents at least 28 additional affected relatives with co‐segregating BAG3 variants.

The variant spectrum includes truncating (nonsense, frameshift, splice) and rare missense changes. A recurrent splice‐site variant, c.508-1G>A, and the hotspot p.Gln161Ter (c.481C>T) have been reported in multiple cohorts, including French‐Canadian families with early‐onset DCM (PMID:25448463). In silico population data confirm absence from large control datasets.

Functional studies demonstrate that BAG3 haploinsufficiency or dominant‐negative effects underlie DCM. Zebrafish bag3 knockdown recapitulates ventricular dilation and HF (PMID:21353195). Transgenic mice expressing human BAG3^P209L develop progressive systolic dysfunction, Z‐disc disintegration, and activation of p38 signaling (PMID:27321750). Human iPSC‐derived cardiomyocytes with heterozygous BAG3 loss show disrupted myofibril structure and impaired contractility (PMID:28724793).

A conflicting mouse knockin model for BAG3^P209L did not develop cardiomyopathy up to 16 months, suggesting species‐specific modifiers or compensation by other BAG family members (PMID:30499714).

Together, these data establish a definitive gene–disease relationship between BAG3 and Dilated Cardiomyopathy. Genetic testing for BAG3 variants enables early diagnosis, familial screening, and tailored management to prevent progression to end‐stage HF.

References

• American journal of human genetics • 2011 • Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. PMID:21353195
• PloS one • 2016 • Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene. PMID:27391596
• The American journal of pathology • 2016 • Cardiomyocyte‐Specific Human Bcl2‐Associated Athanogene 3 P209L Expression Induces Mitochondrial Fragmentation, BAG3 Haploinsufficiency, and Activates p38 Signaling. PMID:27321750
• American journal of physiology. Heart and circulatory physiology • 2019 • P209L mutation in Bag3 does not cause cardiomyopathy in mice. PMID:30499714

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