Loss-of-Function TRPM4 Mutation p.L91Δ Implicated in Progressive Cardiac Conduction Defect

Anne-Flore Hämmerli¹Daniela Ross-Kaschitza¹Prakash Arullampalam¹Anna Shestak²Jimmy Juang³Nada EL Makhzen¹Bianca Sol Soloaga Ricciardi¹Alexandre Francois Edmond Bokhobza¹Jean-sebastien Rougier^1*Elena V. Zaklyazminskaya²Jacek Gajek⁴Can Hasdemir⁵Hugues Abriel¹

• ¹Universitat Bern Institut fur Biochemie und Molekulare Medizin, Bern, Switzerland
• ²Petrovsky National Research Center of Surgery, Moscow, Russia
• ³National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
• ⁴Wroclaw Medical University, Wroclaw, Poland
• ⁵Ege University School of Medicine, Department of Cardiology, Izmir, Türkiye

ABSTRACT Background: The calcium-activated non-specific cation channel TRPM4 mediates membrane depolarization of many cell types, including cardiomyocytes and Purkinje cells. Rare genetic alterations in the TRPM4 gene can cause familial cases of progressive cardiac conduction defects (PCCD). Methods and results: Genetic testing was performed using whole-exome sequencing (WES). Modified human embryonic kidney cells overexpressing either wild-type or variant p.L91Δ human TRPM4 were used to investigate the biochemical and functional consequences of this deletion. Western blots and biotinylation experiments revealed a significant reduction in the expression of the mutant channel compared to the wild-type. Functional experiments using the patch clamp approach demonstrated a significant decrease in the TRPM4 current, consistent with the biochemical observations. Conclusions: The new TRPM4 in-frame deletion p.L91Δ, found in two unrelated patients with a consistent phenotype, triggers a significant decrease in the expression of the channel, leading to its loss of function in the heterologous expression system.