Primary carnitine deficiency – diagnosis after heart transplantation: Better late than never!

Grünert, Sarah C.; Tucci, Sara; Schumann, Anke; Schwendt, Meike; Gramer, Gwendolyn; Hoffmann, Georg F.; Erbel, Michelle; Stiller, Brigitte; Spiekerkoetter, Ute

doi:10.21203/rs.2.22019/v1

Cited by 1 publication

(1 citation statement)

References 17 publications

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“…Of note, markers of activated fibroblasts in this study (POSTN, FN1, FAP, NOX4) overlap substantially with the fibroblast signatures in two failing heart snRNA seq DCM studies 46,47 . Interestingly, the central role of fibroblasts in this hiPSC-CM PCD model is paralleled by clinical findings of strong myocardial fibrosis in PCD patients 6,48,49 .…”

Section: Discussionmentioning

confidence: 73%

Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel disease mechanism

Loos

Klampe

Schulze

et al. 2022

Preprint

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Primary carnitine deficiency (PCD) is an autosomal recessive monogenic disorder caused by mutations in SLC22A5. This gene encodes for OCTN2 which transports the essential metabolite carnitine into the cell. PCD patients suffer from muscular weakness and dilated cardiomyopathy. Detailed molecular disease mechanisms remain unclear. Two OCTN2-defective human induced pluripotent stem cell lines were generated from a healthy control line, carrying a full OCTN2-knockout and a homozygous OCTN2 (N32S) loss of function mutation. OCTN2-defective genotypes showed lower cardiac differentiation efficiency, lower force development, and resting length in engineered heart tissue format compared to isogenic control. Force was sensitive to fatty acid-based media and associated with lipid accumulation, mitochondrial alteration, higher glucose uptake, and metabolic remodelling, replicating findings in animal models. Importantly, genome wide analysis and pharmacological inhibitor experiments identified ferroptosis, an iron- and lipid-dependent cell death pathway linked to fibroblast activation as a novel PCD cardiomyopathy disease mechanism.

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Section: Discussionmentioning

confidence: 73%

Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel disease mechanism

Loos

Klampe

Schulze

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Primary carnitine deficiency – diagnosis after heart transplantation: Better late than never!

Abstract: Background Primary carnitine deficiency due to mutations in the OCTN2 gene is a rare but well-

Cited by 1 publication

References 17 publications

Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel disease mechanism

Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel disease mechanism

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