Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

Truszkowska, Grażyna; Bilińska, Zofia T.; Muchowicz, Angelika; Pollak, Agnieszka; Biernacka, Anna; Kozar-Kamińska, Katarzyna; Stawiński, Piotr; Gasperowicz, Piotr; Kosińska, Joanna; Zieliński, Tomasz; Płoski, Rafał

doi:10.1038/s41598-017-03189-8

Cited by 32 publications

(19 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of the novel genes harboring deleterious protein-coding variants, two genes, NRAP and FHOD3, emerged as strong candidates. Both are important in the maintenance of sarcomeric and actin cytoskeleton in the heart and have been associated with CMP in mouse studies and small case series [36][37][38][39][40][41][42][43]59,60 . Our proband was homozygous for a LoF variant in NRAP similar to a previously reported family with an autosomal recessive DCM phenotype 39 .…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

Lesurf

Said

Akinrinade

et al. 2020

Preprint

View full text Add to dashboard Cite

Cardiomyopathy (CMP) is a heritable genetic disorder. Protein-coding variants account for 20 to 30 percent of cases. The contribution of variants in noncoding DNA elements that regulate gene expression has not been explored. We performed whole genome sequencing (WGS) of 228 unrelated CMP families. Besides pathogenic protein coding variants in known CMP genes, 5% cases harbored rare loss of function variants in novel cardiac genes, with NRAP and FHOD3 being strong candidates. WGS also revealed a high burden of high risk variants in promoters and enhancers of CMP genes in an additional 20 percent cases (Odds ratio 2.14, 95 percent CI 1.60-2.86, p equals 5.26E-07 vs 1326 controls) with genes involved in alpha-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) specifically enriched for regulatory variants (False discovery rate less than 0.03). These findings were independently replicated in the Genomics England CMP cohort (n=1266). The functional effect of non-coding variants on transcription was functionally validated in patient myocardium and reporter assays in human cardiomyocytes, and that of novel gene variants in zebrafish knockouts. Our results show that functionally active variants in novel genes and in regulatory elements of CMP genes contribute strongly to the genomic etiology of childhood-onset CMP.

show abstract

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

Lesurf

Said

Akinrinade

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…During development, NRAP is involved in the myofibrillar assembly in the embryonic murine heart 21 . Interestingly, a patient with dilated cardiomyopathy with biventricular failure was recently found to have a homozygous truncating mutation (rs201084642) which introduced a stop codon to all NRAP isoforms 22 . Although relatively little is known about this gene, our study highlights its clear importance in embryonic development and its potential role in cardiac disease.…”

Section: Discussionmentioning

confidence: 99%

The developmental transcriptome of the human heart

Pervolaraki

Dachtler

Anderson

et al. 2018

Sci Rep

View full text Add to dashboard Cite

The human heart develops through complex mechanisms producing morphological and functional changes during gestation. We have recently demonstrated using diffusion tensor MRI that over the relatively short space of 40 days, between 100–140 days gestational age, the ventricular myocardium transforms from a disorganised tissue to the ordered structure characteristic of mature cardiac tissue. However, the genetic basis underpinning this maturation is unclear. Herein, we have used RNA-Seq to establish the developmentally-regulated transcriptome of gene expression in the developing human heart across three gestational ages in the first and second trimester. By comparing 9 weeks gestational age (WGA) with 12 WGA, we find 288 genes show significant differential expression. 305 genes were significantly altered comparing 12 and 16 WGA, and 806 genes differentially expressed between 9 and 16 WGA. Network analysis was used to identify genetic interactions, node properties and gene ontology categories. In summary, we present a comprehensive transcriptomic analysis of human heart development during early gestation, and identify differentially expressed genes during heart development between 9 and 16 weeks, overlapping the first and early second trimester.

show abstract

“…Overexpression of NRAP in the murine heart results in right ventricular cardiomyopathy, with little effect on the left ventricle and intercalated disc structure, questioning the role of N-RAP in the disease (Lu et al 2011 ). A rare truncating mutation in N-RAP (Arg1502*) which severely reduces protein levels was found in a patient who developed dilated cardiomyopathy in response to a viral illness (Truszkowska et al 2017 ). The same homozygous mutation was carried by his healthy sibling, suggesting that the Arg1502* N-RAP mutation has low penetrance and might require other factors to cause disease (Truszkowska et al 2017 ).…”

Section: Mechanosensing and Transduction At The Idmentioning

confidence: 99%

“…A rare truncating mutation in N-RAP (Arg1502*) which severely reduces protein levels was found in a patient who developed dilated cardiomyopathy in response to a viral illness (Truszkowska et al 2017 ). The same homozygous mutation was carried by his healthy sibling, suggesting that the Arg1502* N-RAP mutation has low penetrance and might require other factors to cause disease (Truszkowska et al 2017 ).…”

Section: Mechanosensing and Transduction At The Idmentioning

confidence: 99%

The intercalated disc: a mechanosensing signalling node in cardiomyopathy

Pruna

Ehler

2020

Biophys Rev

View full text Add to dashboard Cite

Cardiomyocytes, the cells generating contractile force in the heart, are connected to each other through a highly specialised structure, the intercalated disc (ID), which ensures force transmission and transduction between neighbouring cells and allows the myocardium to function in synchrony. In addition, cardiomyocytes possess an intrinsic ability to sense mechanical changes and to regulate their own contractile output accordingly. To achieve this, some of the components responsible for force transmission have evolved to sense changes in tension and to trigger a biochemical response that results in molecular and cellular changes in cardiomyocytes. This becomes of particular importance in cardiomyopathies, where the heart is exposed to increased mechanical load and needs to adapt to sustain its contractile function. In this review, we will discuss key mechanosensing elements present at the intercalated disc and provide an overview of the signalling molecules involved in mediating the responses to changes in mechanical force. Keywords Cardiomyopathy. Mechanobiology. Cell-cell contact. Intercalated disc. Cytoskeleton Mechanical cues in the heart Mechanical stimuli play a key role in both heart morphogenesis and in the mature heart. During heart development, mechanical forces orchestrate the molecular and cellular changes that transform the linear tubular heart into a multichambered machine with four valves (Lindsey et al. 2014). In the chick embryo, primordial heart contraction and the resulting pulsatile blood flow occurs before active oxygen transport is required (Burggren 2004), suggesting that contractile force is required not only for blood pumping but also for morphogenesis. Internal forces from cardiac contraction exert strain on the cell-cell junctions, whereas blood flow exerts both perpendicular (cyclic strain) and parallel forces (shear stress) to the vessel wall (Granados-Riveron and Brook 2012). In the developing heart, these mechanical forces are essential for shaping the chambered structure as well as for myofibrillogenesis (Geach et al. 2015), whereas in the fully formed heart, these cues are important in maintaining the structural and functional integrity of the myocardium. In cardiomyopathies, increased mechanical load triggers compensatory molecular and cellular changes temporarily allowing the myocardium to sustain pump function, but with time, these adaptive responses fail to meet the increased demand, resulting in cardiac dysfunction and heart failure (reviewed in Harvey and Leinwand 2011; McNally et al. 2013). Cardiomyocyte cytoarchitecture Cells that make up the contractile tissue of the heart, the cardiomyocytes, are characterised by a highly regular architecture of cytoskeletal elements to ensure force generation and transduction with each heartbeat (reviewed in Ehler 2016). Cytoskeletal elements are organised into two major multiprotein complexes: the myofibrils and the intercalated disc (Fig. 1). Myofibrils, consisting of thin, thick and elastic filaments, contain the contractile machine...

show abstract

Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

Cited by 32 publications

References 18 publications

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

The developmental transcriptome of the human heart

The intercalated disc: a mechanosensing signalling node in cardiomyopathy

Contact Info

Product

Resources

About