A TMEM175 Mutation Disrupts the Lysosomal-Mitochondrial Axis Causing Short QT Syndrome and Sudden Cardiac Death

A novel TMEM175 p.Arg377His mutation in 7 SQTS patients and their family is linked to shortened QT intervals and increased arrhythmia susceptibility.

• Why it matters: Most SQTS cases lack an identified genetic cause, and known mutations are mainly in surface membrane ion channels, leaving lysosomal mechanisms underexplored.
• What they did: Whole-exome sequencing and rare-variant burden testing in ~118,000 UK Biobank participants were followed by CRISPR-engineered mice and patient-specific iPSC-derived cardiomyocytes to test electrophysiology and mitochondrial function.
• The result: TMEM175R377H disrupted lysosomal–mitochondrial interactions, reducing maximal respiration and spare respiratory capacity and lowering ATP, which coincided with hastened repolarization, APD abbreviation, and higher arrhythmia susceptibility.

AI summary of the abstract · may contain errors · not medical advice · read the paper.