| Autor: |
Sabrina Meisgen, Malin Hedlund, Aurelie Ambrosi, Lasse Folkersen, Vijole Ottosson, David Forsberg, Gudny Ella Thorlacius, Luca Biavati, Linn Strandberg, Johannes Mofors, Daniel Ramskold, Sabrina Ruhrmann, Lauro Meneghel, William Nyberg, Alexander Espinosa, Robert Murray Hamilton, Anders Franco-Cereceda, Anders Hamsten, Tomas Olsson, Lois Greene, Per Eriksson, Kristina Gemzell-Danielsson, Stina Salomonsson, Vijay K Kuchroo, Eric Herlenius, Ingrid Kockum, Sven-Erik Sonesson, Marie Wahren-Herlenius |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Annals of the Rheumatic Diseases |
| Popis: |
ObjectiveNeonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function.MethodsA genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography.ResultsWe identifiedDNAJC6as a novel fetal susceptibility gene, with decreased cardiac expression ofDNAJC6associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded byDNAJC6, have abnormal connectivity and Ca2+homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals.ConclusionsOur study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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