We investigated the involvement of desmin in the cardiomyopathy caused by the lamin A/C gene mutation using the Lmna<sup>H222P/H222P</sup> mouse model of the disease.
Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy.
Immunohistochemistry was compatible with inherited arrhythmogenic cardiomyopathy/dysplasia, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, and some other membrane proteins, as well, and desmin aggregates in transfected cells expressing the mutant desmin.
IOD was significantly different between dilative cardiomyopathy cases and controls and also, overall desmin expression area was increased in dilatative cardiomyopathy patients.
Mutations in the small heat shock protein chaperone CRYAB (αB-crystallin/HSPB5) and the intermediate filament protein desmin, phenocopy each other causing cardiomyopathies.
Cardiomyopathies associated with lamin A/C (n = 5), sarcomeric (n = 8), and desmin (n = 3) mutations all showed a different pattern from that of the desmosomal and PLN mutation carriers.
Thus, in addition to conventional histological identification of protein aggregates, specific desmin peptides show a marked difference in quantity and localization in a tissue section of desmin-related cardiomyopathy and differentiate from other cardiomyopathies.
Our data demonstrated that canonical Wnt/β-catenin signaling was activated through nuclear accumulation of β-catenin in idiopathic dilated cardiomyopathy, ischemic heart disease, and murine desmin-related cardiomyopathy when compared with nonfailing controls and transcription factor 7-like 2 (TCF7L2) was the main β-catenin partner of the T-cell factor (TCF) family in adult hearts.
Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation.
In human, mutations affecting desmin expression or promoting its aggregation lead to skeletal (desmin-related myopathies), or cardiac (desmin-related cardiomyopathy) phenotypes, or both.
Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies.
This report describes the first case of desmincardiomyopathy with early manifestation in adolescence and transformation of several clinical phenotypes over time, representing sufficient difficulties for the correct clinical diagnosis and treatment of the disease at an early stage.
Sildenafil treatment significantly increased myocardial PKG activity and significantly reduced myocardial accumulation of CryAB(R120G), ubiquitin conjugates, and aberrant protein aggregates in mice with CryAB(R120G)-based desmin-related cardiomyopathy.
Collectively, these diseases constitute a rare autosomal-dominant inherited disorder called α-crystallinopathy (crystallinopathy), also known as desmin-related cardiomyopathy.
Furthermore, PA28α knockdown promoted, whereas PA28α overexpression attenuated, accumulation of the mutant protein associated with desmin-related cardiomyopathy in cultured cardiomyocytes.