What question did this study set out to answer?

To determine the molecular mechanism by which the TMEM63B I475del pathogenic deletion alters mechanosensitive channel gating and lipid scramblase activity.

July 17, 2026The Journal of General PhysiologyOpen Access

A TMEM63B variant with enhanced mechanosensitive channel activity and acquired lipid scramblase function

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Authors

ALAugustus J. LowryDuke University PLPengfei LiangCentral South University MTMaria A. Gonzalez TorresDuke University

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Implication

Functional analysis reveals that TMEM63B I475del drives ion leakage and lipid scrambling, highlighting a progressive gate-destabilization mechanism in encephalopathy.

Key Points

To determine the molecular mechanism by which the TMEM63B I475del pathogenic deletion alters mechanosensitive channel gating and lipid scramblase activity.
Characterized electrophysiological properties, mechanosensitivity, and baseline leak currents of the TMEM63B I475del deletion variant compared to V44M and T481N mutants.
Measured phospholipid scramblase activity in cells expressing TMEM63B variants at baseline and following hypotonic osmotic stress.
Engineered mutations at key residues governing gating conformational changes to evaluate their impact on gain-of-function ion and lipid permeation.
The I475del channel displayed basal leak currents, enhanced mechanically activated currents, and elevated mechanosensitivity, establishing it as a gain-of-function mechanosensitive variant.
I475del conferred constitutive phospholipid scramblase activity that was uniquely potentiated under hypotonic osmotic stress compared to V44M and T481N.
Mutating gating-control residues abolished both the gain-of-function ion currents and the acquired lipid scramblase transport through I475del.

Cite This Study

Lowry et al. (2026) studied this question.

synapsesocial.com/papers/6a9fb72b516c2ec66e7c650d https://doi.org/10.1085/jgp.202614003

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Implication

Functional analysis reveals that TMEM63B I475del drives ion leakage and lipid scrambling, highlighting a progressive gate-destabilization mechanism in encephalopathy.

A TMEM63B variant with enhanced mechanosensitive channel activity and acquired lipid scramblase function

Discussion

Member takes

Implication

Key Points

Cite This Study

A TMEM63B variant with enhanced mechanosensitive channel activity and acquired lipid scramblase function

Discussion

Member takes

Implication

Key Points

Cite This Study

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