SHANK3 proteins interact with various receptors and cytoskeletal elements, orchestrating synaptic function and structural plasticity. Compared to SHANK3’s well-known functions in the field of neuroscience, the specific physiological functions of SHANK3 in non-neuronal tissues remain less understood, warranting further investigation, particularly in cardiac function.4)

Several key studies have uncovered diverse cardiac phenotypes associated with Shank3 mutations in mice. Shank3 mutant models, including knock-out (KO), overexpression, and conditional mutants, exhibit varied cardiac outcomes, often linked to specific exon deletions and isoforms of Shank3. Shank3 mutant mice with specific exon deletions (e.g., Δexon 4–9 KO) showed alterations in cardiac morphology, such as increased left ventricular (LV) wall thickness, although other parameters like heart rate and LV fractional shortening remained unaffected.5) These findings suggest that different Shank3 isoforms contribute to distinct aspects of cardiac physiology.

Interestingly, Shank3 dosage plays a critical role in myocardial infarction-induced cardiac dysfunction. While Shank3 KO mice experience worsened outcomes, including larger infarct size and reduced cardiac function, Shank3 overexpression appears to protect the heart by reducing apoptosis and enhancing autophagy in cardiomyocytes.6) These effects were observed both in vivo and in primary neonatal cardiomyocytes, highlighting Shank3’s protective role against cardiac stress.

In the context of aging heart, increased Shank3 expression has been linked to age-related cardiac dysfunction. Aged wild-type mice showed hypertrophy, fibrosis, and elevated mitochondrial oxidative stress, which were alleviated in cardiac-specific Shank3 KO mice. Shank3 influences mitochondrial function by modulating Ca²⁺/calmodulin-dependent protein kinase II translocation and the Parkin-mediated mitophagy.7) This suggests that elevated Shank3 levels in aging hearts may impair protective mitophagy pathways, leading to increased apoptosis and dysfunction.

Recent findings have expanded the clinical significance of SHANK3 beyond neurodevelopmental disorders, underscoring its impact on cardiovascular health.8) In a prospective study, patients with pathogenic SHANK3 variants were found to have an elevated risk of cardiac issues, including myocardial dysfunction, congenital heart disease, and cases of postictal atrial fibrillation. This research highlights that, even at a young age, SHANK3 mutation carriers may experience significant cardiovascular abnormalities, suggesting a need for proactive cardiac evaluations as part of routine care. Given the association with risks like heart failure and sudden unexpected death in epilepsy, integrating cardiovascular monitoring into multidisciplinary care could facilitate early detection and intervention, potentially improving patient outcomes. Further studies are warranted to uncover the mechanisms driving these cardiac manifestations in SHANK3 mutation carriers.

Overall, these studies reveal a complex, context-dependent role for Shank3 in cardiac physiology, showing both protective and detrimental effects depending on the pathological state and developmental stage. However, comprehensive omics-based analyses on Shank3’s regulation of cardiac function, potential cardiac regulatory targets, and the precise mechanisms involved remain unclear.

In this issue of the Korean Circulation Journal, Ko et al.9) uncovers a novel role for Shank3 in the heart, emphasizing its involvement in calcium homeostasis and contractile function. Shank3-overexpressing transgenic mice exhibited notable cardiac phenotypes, including reduced heart weight, increased fibrosis, arrhythmias, and sudden cardiac death (Figure 1). These findings align with electrophysiological changes, such as prolonged action potentials and increased L-type Ca²⁺ channel currents in cardiomyocytes. Despite normal sarcoplasmic reticulum Ca²⁺ levels, the cytosolic Ca²⁺ transients were elevated, with prolonged decay, suggesting a disruption in calcium handling (Figure 1). Interestingly, cell shortening, a key indicator of cardiac contractility, was enhanced in the transgenic cardiomyocytes, hinting at hypercontractility as a maladaptive response.

The cardiac Shank3 interactome revealed 78 proteins, pointing to Shank3’s involvement in diverse molecular pathways within the heart. Of particular interest was the down-regulation of Troponin I, a critical protein in cardiac muscle contraction regulation, which likely contributes to the contractile abnormalities observed in these mice. In this study, the interactome analysis of Shank3 in Shank3-overexpressing hearts demonstrated only a reduction in Troponin I. However, the diversity of biological pathways revealed through network analysis of the interactome, particularly those associated with mitochondrial function and its relationship with Shank3, is highly intriguing. These findings underscore the need for further in-depth studies to elucidate various roles of Shank3 in mitochondrial-based energy metabolism regulation.

In conclusion, Ko et al.’s research9) provides a groundbreaking perspective on the role of Shank3 beyond its well-established neuropsychiatric functions. By focusing on its overexpression in cardiomyocytes, the authors have expanded our understanding of SHANK3 as a target in cardiac diseases related to calcium handling abnormalities, such as arrhythmias and heart failure.