A study published in the European Journal of Human Genetics is shedding new light on the expanding role of the HSPB8 gene in neuromuscular disorders, and potentially, in cardiac disease. Researchers have identified three previously unreported genetic mutations in HSPB8 in patients with early-onset myopathy, revealing a surprising connection between the gene and cardiac dysfunction, a relationship not strongly established until now.
The study examined three individuals with severe muscle weakness beginning in childhood or early adulthood. What sets these cases apart is the concurrent involvement of respiratory muscles and, in two instances, cardiomyopathy.
Until recently, HSPB8 gene variants were predominantly associated with hereditary motor neuropathies and various forms of myopathy. These conditions typically involve muscle weakness but stop short of affecting the heart.
This new study, however, identified three novel frameshift mutations, c.562delC, c.520_523delTACT, and c.515delC, that are correlated with early-onset disease and, notably, heart muscle dysfunction. The findings challenge prior assumptions about the gene’s role and suggest that certain mutations might affect not just skeletal muscle and neurons, but also striated muscle in the heart.
In the most severe case, a young man developed progressive weakness in his 20s, which ultimately led to respiratory failure and heart complications that contributed to his death in his 30s. A second patient, a child diagnosed with Kawasaki syndrome, developed restrictive hypertrophic cardiomyopathy, a rare combination that raises questions about potential genetic and inflammatory interplay. A third patient showed no signs of heart dysfunction, but had significant skeletal muscle involvement and respiratory insufficiency.
The researchers noted that these new mutations result in a C-terminal extension of the HSPB8 protein, a feature that appears to affect how the protein behaves in cells. In particular, the altered protein has a tendency to aggregate, disrupting cellular quality control mechanisms responsible for disposing of misfolded proteins.
Interestingly, some previously identified HSPB8 mutations with similar extensions had no visible aggregation in muscle tissue, suggesting that the length and composition of these extensions may influence disease severity. These new variants, however, seem to produce longer and more hydrophobic extensions, which may drive abnormal clumping of the protein and interfere with cell function, including in heart muscle cells.
The article also draws parallels with related proteins. Other small heat shock proteins, such as HSPB5, HSPB6, and HSPB7, have known ties to cardiomyopathy. In addition, BAG3, a protein that partners with HSPB8, has established roles in both myopathy and heart disease. Taken together, the findings suggest that HSPB8 should be considered in the genetic evaluation of patients with unexplained cardiomyopathy, particularly when accompanied by muscle symptoms.
Animal studies referenced in the paper add further weight to the hypothesis. Mice engineered to overexpress mutant forms of HSPB8 in heart tissue showed signs of mild cardiac disease, while knockout models only developed symptoms under stress or aging, echoing the variability seen in human patients.
While rare, these cases underscore the interconnectedness of genetic diseases, where mutations in a single gene can manifest across different organ systems. As whole-exome sequencing becomes more routine in neurology and cardiology, such cross-system findings are likely to become more common, and more critical to understand.