Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-19312 Wissenschaftlicher Artikel Brodehl, Andreas; Pour Hakimi, Seyed Ahmad; Stanasiuk, Caroline; Ratnavadivel, Sandra; Hendig, Doris; Gaertner, Anna; Gerull, Brenda; Gummert, Jan; Paluszkiewicz, Lech; Milting, Hendrik Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations. 2019 Genes 10 11 urn:nbn:de:bvb:20-opus-193121 10.3390/genes10110918 Medizinische Klinik und Poliklinik I OPUS4-28527 Wissenschaftlicher Artikel Brodehl, Andreas; Meshkov, Alexey; Myasnikov, Roman; Kiseleva, Anna; Kulikova, Olga; Klauke, Bärbel; Sotnikova, Evgeniia; Stanasiuk, Caroline; Divashuk, Mikhail; Pohl, Greta Marie; Kudryavtseva, Maria; Klingel, Karin; Gerull, Brenda; Zharikova, Anastasia; Gummert, Jan; Koretskiy, Sergey; Schubert, Stephan; Mershina, Elena; Gärtner, Anna; Pilus, Polina; Laser, Kai Thorsten; Sinitsyn, Valentin; Boytsov, Sergey; Drapkina, Oxana; Milting, Hendrik Hemi- and homozygous loss-of-function mutations in DSG2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases. 2021 International Journal of Molecular Sciences 22 7 urn:nbn:de:bvb:20-opus-285279 10.3390/ijms22073786 Medizinische Klinik und Poliklinik I