A homozygous DSC2 deletion associated with arrhythmogenic cardiomyopathy is caused by uniparental isodisomy

• Published in: Journal of molecular and cellular cardiology Vol. 141; pp. 17 - 29
• Main Authors: Brodehl, Andreas, Weiss, Jürgen, Debus, Jana Davina, Stanasiuk, Caroline, Klauke, Bärbel, Deutsch, Marcus André, Fox, Henrik, Bax, Jördis, Ebbinghaus, Hans, Gärtner, Anna, Tiesmeier, Jens, Laser, Thorsten, Peterschröder, Andreas, Gerull, Brenda, Gummert, Jan, Paluszkiewicz, Lech, Milting, Hendrik
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2020
• Subjects: Arrhythmogenic right ventricular cardiomyopathy; Cardiomyopathy; Desmocollin-2; Desmosomes; DSC2; Uniparental Isodisomy; PBS; Desmocollin-2; NMD; WES; Arrhythmogenic right ventricular cardiomyopathy; CGH; IHC; MRI; Cardiomyopathy; Uniparental Isodisomy; qRT-PCR; ECG; TBST; UPD; Desmosomes; ROH; ACM; GFP; hiPSC; PEI; TEM; EYFP; PTC; DSC2
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.03.006

We aimed to unravel the genetic, molecular and cellular pathomechanisms of DSC2 truncation variants leading to arrhythmogenic cardiomyopathy (ACM).
We report a homozygous 4-bp DSC2 deletion variant c.1913_1916delAGAA, p.Q638LfsX647hom causing a frameshift carried by an ACM patient. Whole exome sequencing and comparative genomic hybridization analysis support a loss of heterozygosity in a large segment of chromosome 18 indicating segmental interstitial uniparental isodisomy (UPD). Ultrastructural analysis of the explanted myocardium from a mutation carrier using transmission electron microscopy revealed a partially widening of the intercalated disc. Using qRT-PCR we demonstrated that DSC2 mRNA expression was substantially decreased in the explanted myocardial tissue of the homozygous carrier compared to controls. Western blot analysis revealed absence of both full-length desmocollin-2 isoforms. Only a weak expression of the truncated form of desmocollin-2 was detectable. Immunohistochemistry showed that the truncated form of desmocollin-2 did not localize at the intercalated discs. In vitro, transfection experiments using induced pluripotent stem cell derived cardiomyocytes and HT-1080 cells demonstrated an obvious absence of the mutant truncated desmocollin-2 at the plasma membrane. Immunoprecipitation in combination with fluorescence measurements and Western blot analyses revealed an abnormal secretion of the truncated desmocollin-2.
In summary, we unraveled segmental UPD as the likely genetic reason for a small homozygous DSC2 deletion. We conclude that a combination of nonsense mediated mRNA decay and extracellular secretion is involved in DSC2 related ACM.
•We show that DSC2 truncating mutations cause a loss of function mechanism.•DSC2 truncating mutations can be recessively inherited.•First report, demonstrating that uniparental isodisomy might be involved in ACM.