RBM20 (RNA-binding motif protein 20) is a splicing factor targeting multiple cardiac genes, and its mutations cause cardiomyopathies. Originally, RBM20 mutations were discovered to cause the development of dilated cardiomyopathy by erroneous splicing of the gene TTN (titin). Titin is a giant protein found in a structure of the sarcomere that functions as a molecular spring and provides a passive stiffness to the cardiomyocyte. Later, RBM20 mutations were also described in association with arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Here, we present a clinical case of a rare arrhythmogenic phenotype and no structural cardiac abnormalities associated with a RBM20 genetic variant of uncertain significance.
Alterations in the proteostasis network and accumulation of misfolded protein aggregates — is one of the new pathogenesis concepts of chronic heart failure. We hypothesis in addition to well-known transthyretin (ATTR) and AL-amyloidosis some patients may represent amyloid lesion in myocardium came from undescribed amyloidogenic precursors due to misfolding of myocardial structural proteins.Here, we report on the case of patient with hypertrophic and restrictive phenotype of cardiomyopathy, biventricular heart failure, considered for heart transplant, and excluded known types of amyloidosis. Genetic testing revealed extended deletion in the gene of giant protein titin (TTN).We present with the use of bioinformatic analysis and molecular modeling how this mutation could lead to unfolding of corresponding protein and open its amyloidogenic motifs for intermolecular interactions, therefore, provide amyloidogenic ability. This data enables in more detail to decipher the pathogenesis of chronic heart failure on the background of cardiomyopathy, planning further studies for development of personalized risk profiling in different types of amyloidosis and elaborate more personalized treatment approach for such patients in the future.
Background. Sarcomere protein genes such as MYBPC3, FLNC, TTN, RBM20 are associated with cardiomyopathies (CMP). A large number of rare genetic variants complicates the interpretation genetic studies and assessing the pathogenicity. Moreover, there is a lack of an information about rare variants frequency in a healthy Russian population. Polymorphisms in these genes often act as modifiers, aggravating the clinical course of CMP caused by mutations in other genes.Objective. To compare the frequency of rare (less than 0.1 %) missense and truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the patients with CMP and in the general population.Design and methods. The CMP group included 251 patients. The control group included 192 men (from the ESSE-RF study). A molecular genetic examination was performed using high-processive sequencing technology, followed by verification by Sanger sequencing.Results. The frequency of truncating variants in the genes TTN, FLNC, MYBPC3, RBM20 in the group with CMP was 7.17 %, and missense variants — 56.6 %: 11.5 % were pathogenic/likely pathogenic, 39.5 % — variants of uncertain significance, 49 % — probably benign/benign. The frequency of truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the control group was 0.52 %, and the frequency of missense variants was 15.1 %: 38 % were variants of uncertain significance, 62 % — probably benign/benign.Conclusion. Frequency of missense and truncating variants with a frequency of less than 0.1 % in the TTN, FLNC, MYBPC3, RBM20 genes was increased in the group of patients with CMP.
Background. Gene TTN associated with all types of cardiomyopathy, however its large size (294 b.p.) warrants a lot of individual unique genetic variants or variants with low frequency, that aggravates their interpretation. Besides that nowadays there is no data about spectrum of variants in this gene in healthy Russian population. Recognition frequency and spectrum of variants in gene TTN in healthy Russian population will allow us to use it for interpretation results of molecular genetic research for patients with different heart pathology, and define prognosis for different heart diseases.Objective. Recognize frequency and spectrum of single nucleotide and truncating variants in gene TTN in healthy Russian population and compare it with international data bases, and evaluate level of pathogenicity these variants and their distributing across titin structure.Design and methods. 192 men in age 55,8±6,6 years were tested with next-generation sequencing. Identified genetic variants were confirmed by Sanger sequencing. Results. Allele missense variant frequency (with frequency less than 0.1%) in TTN in healthy Russian population amount to 15.1 %, and truncating variants — 0.52 %. 37,9 % of them were variants of unknown significance, 62 % — likely-benign and 0.1 % — benign. There was no pathological and likely-pathological variants. Identified genetic variants distributed throughout the titin structure.Conclusion. Received result is congruent с international data bases and researches. Expended laboratory method (Next generation sequencing and confirmation with Sanger sequencing) can be used both in clinical practice, and in creating data bases of genetic variants in healthy Russian population.
РезюмеРанее считалось, что мутации в структуре гена филамина С способны вызывать только скелетные миопатии, сердечные ткани при этом не исследовались. Однако недавно были обнаружены филаминовые мутации, которые приводят как к сочетанным повреждениям скелетной и сердечной мускулатуры, так и изолированному поражению сердечной ткани. Более того, в настоящее время стало известно, что мутации в FLNC ассоциированы со всеми известными видами кардиомиопатий (ГКМП, ДКМП, РКМП, аритмогенной). В статье представлены собственные клинические наблюдения взрослого и детского случаев изолированной филаминовой РКМП на базе нашего учреждения. Изучение данной проблемы в дальнейшем позволит включить известные нам мутации в скрининговые панели, что приведет к ранней диагностике кардиомиопатий, ассоциированных с мутациями в FLNC, возможности предотвращения быстрого прогрессирования заболевания, а также к более поздним срокам трансплантации сердца.Ключевые слова: рестриктивная кардиомиопатия, FLNC, филамин С.Для цитирования: Полубояринова О.Ю., Князева А.А., Мельник О.В., и соавт. Филаминовая рестриктивная кардиомиопатия: о чём следует знать. Трансляционная медицина. 2018; 5 (3): 15-22.
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