Exploring the Crosstalk Between LMNA and Splicing Machinery Gene Mutations in Dilated Cardiomyopathy

Abstract

Mutations in the LMNA gene, which encodes for the nuclear lamina proteins lamins A and C, are responsible for a diverse group of diseases known as laminopathies. One type of laminopathy is Dilated Cardiomyopathy (DCM), a heart muscle disease characterized by dilation of the left ventricle and impaired systolic function, often leading to heart failure and sudden cardiac death. LMNA is the second most commonly mutated gene in DCM. In addition to LMNA, mutations in more than 60 genes have been associated with DCM. The DCM-associated genes encode a variety of proteins including transcription factors, cytoskeletal, Ca2+-regulating, ion-channel, desmosomal, sarcomeric, and nuclear-membrane proteins. Another important category among DCM-causing genes emerged upon the identification of DCM-causing mutations in RNA binding motif protein 20 (RBM20), an alternative splicing factor that is chiefly expressed in the heart. In addition to RBM20, several essential splicing factors were validated, by employing mouse knock out models, to be embryonically lethal due to aberrant cardiogenesis. Furthermore, heart-specific deletion of some of these splicing factors was found to result in aberrant splicing of their targets and DCM development. In addition to splicing alterations, advances in next generation sequencing highlighted the association between splice-site mutations in several genes and DCM. This review summarizes LMNA mutations and splicing alterations in DCM and discusses how the interaction between LMNA and splicing regulators could possibly explain DCM disease mechanisms.

A multi-network comparative analysis of transcriptome and translatome in cardiac remodeling

“…In co-expression networks, the top genes are the most connected genes, based on the correlation structure. We identified a number of hub genes that may function as molecular drivers of cardiac remodeling: Gsk3a (Ribo2), characterized for its role in regulating glycogen metabolism, and shown to be a critical player in cardiac hypertrophy (Sugden et al, 2008;Zhou et al, 2016); Cand2 (Ribo2), a mTOR dependent mRNA recently identified as a growth regulator, upregulated in the acute phase of cardiac hypertrophy (Sandmann et al, 2018); Vldlr (RNA2), characterized for its role in obesity associated lipotoxicity (Fungwe et al, 2019), and negatively associated with survival in the ischemic heart (Perman et al, 2011); Eif3d (Ribo14), thought to be involved in cap-dependent translation during cellular stress, independently of Eif4e (Lee et al, 2016); Immt (Ribo15), a mitochondrial membrane protein whose transcript is regulated by Rbm20 (Zahr and Jaalouk, 2018); Ncoa6 (RNA16), whose dysfunction is linked to dilated cardiomyopathy in mouse models (Roh et al, 2014); Slc25a3 (RNA14), the absence of which was shown to drive a novel model of metabolic, mitochondrial-driven cardiomyopathy (Kwong et al, 2014); or Zmpste24 (RNA17), which may be implicated in prelamin A toxicity-driven inflammation (Brayson et al, 2019).…”

Variants of RBM20 gene in pediatric patients with dilated cardiomyopathy

“…В 2009г RBM20 был впервые описан в качестве гена, связанного с развитием ДКМП [8,11,[14][15][16][17][18]. Позже было показано, что патогенные варианты этого гена связаны с развитием 2-3% случаев ДКМП во всех возрастных группах [14,15].…”

Genetic mutation of familial dilated cardiomyopathy based on next‑generation semiconductor sequencing

“…LMNA is one of the most common pathogenic genes responsible FDC ( 3 ). At birth, no significant differences in the growth status between LMNA knockout mice ( LMNA −/− ) and wild type mice were reported ( 16 ).…”

“…In addition, DCM has a complex pathogenesis. Genetic screening methods have demonstrated that common variants in numerous genes are present in severe DCM cases, indicating that patients with DCM have complex multi-variant or oligogenic genetic backgrounds ( 1 – 3 ). It has been suggested that up to 50% of idiopathic DCM cases may be attributed to genetic mutations ( 4 ).…”