KLHL24 associated cardiomyopathy: Gene function to clinical management

Background: KLHL24 (Kelch-like protein 24) is a significant component of the ubiquitin-proteasome system (UPS), involved in regulating protein turnover through targeted ubiquitination and degradation. Germline mutations in KLHL24 gene have been known to cause Epidermolysis Bullosa Simplex characterized by skin fragility but has recently been found to cause Cardiomyopathy.

Main body: Various cardiomyopathies, including hypertrophic cardiomyopathy and dilated cardiomyopathy, leading to abnormal protein degradation and affecting the stability and function of essential cardiac proteins which finally results into structural and functional abnormalities in cardiac muscle. In this review, in order to understand the disease association of germline mutations of KLHL24, we summarize all the studies performed with KLHL24 gene including studies from 2016 when KLHL24 was first identified to be associated with epidermolysis bullosa simplex till the recent studies in 2024 by using keywords such as KLHL24 gene, hypertrophic cardiomyopathy, dilated cardiomyopathy and epidermolysis bullosa simplex. Furthermore, we explored the proposed molecular mechanisms and pathophysiologies of KLHL24 associated diseases. Patients with KLHL24 mutations were usually presented with variable clinical symptoms. The main clinical presentations have been cutaneous lesions, cardiac symptoms associated with cardiomyopathies and there have been reports of skeletal muscle weakness and neurological symptoms as well. Current treatments focus on managing clinical symptoms and preventing complications through medications, lifestyle changes, and surgical interventions. In addition, researches have also been conducted cell culture based in vitro studies for reducing the clinical symptoms of KLHL24 associated diseases. However, currently there are no specific clinical trials going on regarding the therapeutic strategies among patients with KLHL24 mutations. Understanding the role of KLHL24 in cardiomyopathies is very important for developing targeted diagnostic approach with therapeutic strategies.

Conclusion: This review emphasizes the importance of KLHL24 mutations as a newly recognized cause of cardiomyopathy, paving the way for improved clinical diagnosis, targeted therapies, and ultimately, for better patient outcomes.