The Desmin Mutation DES-c.735G>C Causes Severe Restrictive Cardiomyopathy by Inducing In-Frame Skipping of Exon-3

Abstract

Currently, little is known about the genetic background of restrictive cardiomyopathy (RCM). Herein, we screened an index patient with RCM in combination with atrial fibrillation using a next generation sequencing (NGS) approach and identified the heterozygous mutation DES-c.735G>C. As DES-c.735G>C affects the last base pair of exon-3, it is unknown whether putative missense or splice site mutations are caused. Therefore, we applied nanopore amplicon sequencing revealing the expression of a transcript without exon-3 in the explanted myocardial tissue of the index patient. Western blot analysis verified this finding at the protein level. In addition, we performed cell culture experiments revealing an abnormal cytoplasmic aggregation of the truncated desmin form (p.D214-E245del) but not of the missense variant (p.E245D). In conclusion, we show that DES-c.735G>C causes a splicing defect leading to exon-3 skipping of the DES gene. DES-c.735G>C can be classified as a pathogenic mutation associated with RCM and atrial fibrillation. In the future, this finding might have relevance for the genetic understanding of similar cases.

Case report: Rare restrictive cardiomyopathy with ventricular fibrillation as initial symptom rescued by automatic external defibrillator in a pediatric patient

“…As research advances, more and more genes related to RCM have been discovered, such as cardiac actin (ACTC1), cardiac myosin binding protein C (MYBPC3), β-myosin heavy chain (MYH7), titin (TTN), troponin T (TNNT2), filamin-C (FLNC), αB-crystallin (CRYAB), desmin (DES), etc. (7)(8)(9)(10)(11)(17)(18)(19). In this boy, we found no other variants in genes associated with RCM, except for TNNI3.…”

“…The major mutations are found in genes encoding for sarcomere proteins, such as cardiac troponins I (TNNI3), alpha tropomyosin (TPM1), titin (TTN), and so on (7). Mutations in non-sarcomeric genes are also relevant, for example in the filamin-C (FLNC), αB-crystallin (CRYAB), and desmin (DES) (8)(9)(10)(11). Here we reported a case of RCM with ventricular fibrillation in a 7-year-old boy who was successfully rescued by AED outside the hospital.…”

Genetic Insights into Primary Restrictive Cardiomyopathy

“…In 2006, Hager and colleagues described for the first time a patient with RCM carrying the mutation DES-p.E245D. Later, it was recognized that this mutation causes a splicing defect leading to an in-frame skipping of exon-3 causing a deletion of 32 amino acids within the rod domain [115,116]. Several other pathogenic RCM-associated DES mutations have been reported [14,[117][118][119][120][121][122] (Figure 5 and Table 4).…”

Desmin variants: Trigger for cardiac arrhythmias?

“…DES variants with a pathogenic single nucleotide polymorphism located in coil 2B or near the carboxyl terminus of the gene, usually result into missense mutations that associate with conduction diseases and arrhythmias (Figure 3; Table 1). Moreover, several studies showed that single nucleotide polymorphisms (SNPs) around DES c.375G leads to a splice variant which excludes exon 3 (p.D214-E245del) (Ojrzyńska et al, 2017;Fan et al, 2019;Brodehl et al, 2021;Chen et al, 2021). The carboxyl tail of desmin has previously been suggested to play an important role in filament-filament interactions, and variations lead to filament flexibility and stiffening of the filament.…”