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

Autor:	Agarwal R; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Wakimoto H; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Paulo JA; Department of Cell Biology (J.A.P., S.P.G.), Harvard Medical School, Boston, MA., Zhang Q; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Reichart D; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Toepfer C; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA.; Radcliffe Department of Medicine (C.T.), University of Oxford, United Kingdom.; Wellcome Centre for Human Genetics (C.T.), University of Oxford, United Kingdom., Sharma A; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA.; Board of Governors Regenerative Medicine Institute (A.S.), Cedars-Sinai Medical Center, Los Angeles, CA.; Smidt Heart Institute (A.S.), Cedars-Sinai Medical Center, Los Angeles, CA.; Department of Biomedical Sciences (A.S.), Cedars-Sinai Medical Center, Los Angeles, CA., Tai AC; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Lun M; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Gorham J; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., DePalma SR; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Gygi SP; Department of Cell Biology (J.A.P., S.P.G.), Harvard Medical School, Boston, MA., Seidman JG; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA., Seidman CE; Department of Genetics (R.A., H.W., Q.Z., D.R., C.T., A.S., A.C.T., M.L., J.G., S.R.D., J.G.S., C.E.S.), Harvard Medical School, Boston, MA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (C.E.S.).; Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2022 Nov 29; Vol. 146 (22), pp. 1674-1693. Date of Electronic Publication: 2022 Nov 02.
DOI:	10.1161/CIRCULATIONAHA.122.059688
Abstrakt:	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 inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function. Conclusions: ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.
Databáze:	MEDLINE
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