Disease-associated amino acid substitutions outside canonical motor motifs impair Myo1e localization and activity
- 1SUNY Upstate Medical University
Abstract
Steroid-resistant nephrotic syndrome (SRNS) is a severe kidney disorder characterized by proteinuria and disruption of glomerular filtration, often driven by genetic defects in genes encoding proteins required for podocyte functions. Among these, MYO1E, encoding the actin- and membrane-associated motor protein Myosin 1e (Myo1e), has been implicated in familial and sporadic forms of SRNS. Here, we investigated two MYO1E missense variants, A92E and G562R, identified in trans in a patient with childhood-onset SRNS and located outside canonical P-loop and switch subdomains of the Myo1e motor domain. Both residues are highly conserved, located within predicted -helices in the motor domain, and replaced by larger charged residues, which may reduce protein stability or folding. In podocyte-derived cells, both mutants failed to localize at intercellular junctions and displayed reduced colocalization with actin. The G562R variant additionally formed cytoplasmic aggregates that were partially expression-level-dependent and exhibited decreased fluorescence recovery after photobleaching, indicating impaired protein dynamics. In vitro motility and ATPase assays indicated that the G562R mutant exhibited a marked loss of ATPase activity while the A92E mutant displayed ATPase activity similar to the WT but was characterized by reduced motility and thermal stability. Together, these results demonstrate that A92E and G562R mutations compromise Myo1e localization and function, supporting their pathogenic role in SRNS.
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BibTeX
@misc{sayeeda2026diseaseassociated,
title = {{Disease-associated amino acid substitutions outside canonical motor motifs impair Myo1e localization and activity}},
author = {K. Sayeeda and J. Ge and C. M. Yengo and M. Krendel},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759198},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759198v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Disease-associated amino acid substitutions outside canonical motor motifs impair Myo1e localization and activity
AU - K. Sayeeda
AU - J. Ge
AU - C. M. Yengo
AU - M. Krendel
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759198
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759198v1
AB - Steroid-resistant nephrotic syndrome (SRNS) is a severe kidney disorder characterized by proteinuria and disruption of glomerular filtration, often driven by genetic defects in genes encoding proteins required for podocyte functions. Among these, MYO1E, encoding the actin- and membrane-associated motor protein Myosin 1e (Myo1e), has been implicated in familial and sporadic forms of SRNS. Here, we investigated two MYO1E missense variants, A92E and G562R, identified in trans in a patient with childhood-onset SRNS and located outside canonical P-loop and switch subdomains of the Myo1e motor domain. Both residues are highly conserved, located within predicted -helices in the motor domain, and replaced by larger charged residues, which may reduce protein stability or folding. In podocyte-derived cells, both mutants failed to localize at intercellular junctions and displayed reduced colocalization with actin. The G562R variant additionally formed cytoplasmic aggregates that were partially expression-level-dependent and exhibited decreased fluorescence recovery after photobleaching, indicating impaired protein dynamics. In vitro motility and ATPase assays indicated that the G562R mutant exhibited a marked loss of ATPase activity while the A92E mutant displayed ATPase activity similar to the WT but was characterized by reduced motility and thermal stability. Together, these results demonstrate that A92E and G562R mutations compromise Myo1e localization and function, supporting their pathogenic role in SRNS.
ER -