A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology.

Stem Cell Reports
Matthew J BirketJean-Michel Itier

Abstract

Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes.

Citations

May 7, 2020·Journal of Clinical Medicine·Abdellah TebaniSoumeya Bekri
Feb 13, 2021·International Journal of Molecular Sciences·Daniela Sorriento, Guido Iaccarino
Feb 21, 2021·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·Yan-Ling SunLi Sun
Feb 20, 2021·Journal of the American College of Cardiology·Maurizio PieroniMehdi Namdar
Sep 9, 2020·Neuroscience Letters·Kritika Mittal, Katrin Schrenk-Siemens
May 18, 2021·Clinical Genetics·Vanessa CastelliClaudio Ferri
Jun 23, 2021·International Journal of Cardiology·Mehdi NamdarPeter Macfarlane
Jul 22, 2021·Molecular Pain·Carina WeissmannOsvaldo D Uchitel
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Datasets Mentioned

BETA
GM00107
GM00881

Methods Mentioned

BETA
FACS
gene knockouts
PCR
gene knockout

Software Mentioned

STRING
limma

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