Pathogenesis of Cardiomyopathy Caused by Variants in <i>ALPK3</i>, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere.

ABSTRACT:

Background

ALPK3 encodes α-kinase 3, a muscle-specific protein of unknown function. ALPK3 loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood.

Methods

We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues.

Results

Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhi

SUBMITTER: Agarwal R 

PROVIDER: S-EPMC9698156 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature