The novel αB‐crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. Issue 8 (21st June 2017)

• Record Type: Journal Article
• Authors: Brodehl, Andreas; Gaertner‐Rommel, Anna; Klauke, Bärbel; Grewe, Simon Andre; Schirmer, Ilona; Peterschröder, Andreas; Faber, Lothar; Vorgerd, Matthias; Gummert, Jan; Anselmetti, Dario; Schulz, Uwe; Paluszkiewicz, Lech; Milting, Hendrik
• Is Part Of: Human mutation. Volume 38:Issue 8(2017)
• Page Start: 947
• Page End: 952
• Publication Date: 2017-06-21
• Subjects: αB‐crystallin -- hypertrophic cardiomyopathy -- intermediate filaments -- restrictive cardiomyopathy -- small heat shock proteins; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23248
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : In this study, we identified in small family with restrictive cardiomyopathy the novel missense mutation CRYAB ‐p.D109G by next‐generation sequencing. CRYAB encodes the small heat shock protein αB‐Crystallin. The mutation p.D109G affects two ionic bridges between the dimer contact sites. We demonstrated that this missense mutation causes an abnormal protein aggregation in vitro and in the explanted myocardial tissue oft the mutation carrier. In summary, we showed that CRYAB mutations could cause beside hypertrophic and dilated cardiomyopathy also restrictive cardiomyopathy. Abstract: Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next‐generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB‐crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant αB‐crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.