Gene TMEM43
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Also known as
Transmembrane Protein 43, LUMA, ARVC5, ARVD5Overview
TMEM43 (Transmembrane Protein 43) encodes a nuclear envelope protein also known as LUMA (Lamin-associated protein UpRegulated by MitogensA). This protein is part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, which physically connects the nuclear lamina to the cytoskeleton. TMEM43 plays important roles in maintaining nuclear envelope structure and integrity, regulating mechanotransduction, and modulating gene expression in response to mechanical stress. The protein is particularly abundant in cardiac and skeletal muscle tissues, where mechanical forces are continuously applied to cells during contraction and relaxation cycles.Mutations in TMEM43 cause arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5), an autosomal dominant cardiac disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, leading to ventricular arrhythmias, heart failure, and sudden cardiac death. The p.S358L founder mutation is particularly well-studied in Newfoundland populations, where it causes a highly penetrant and aggressive form of ARVC with nearly complete penetrance in males. TMEM43-related cardiomyopathy typically presents in adulthood with ventricular arrhythmias and carries significant risk of sudden death, especially during exercise. Genetic testing and family screening are crucial for early identification of at-risk individuals, enabling implementation of preventive measures including lifestyle modifications, medication, and implantable cardioverter-defibrillators.