Abstract
NSUN5, encoding a cytosine-5 RNA methyltransferase and located in the 7q11.23 locus, is a candidate gene for tetralogy of Fallot (TOF). Deletion of the 7q11.23 locus in humans is linked to cardiac outflow tract (OFT) disorders including TOF. We identified four potential pathogenic mutations in the coding region of NSUN5 and which were enriched in TOF patients by an association study of 132 TOF patients and 2,000 in-house controls (P = 1.44 × 10–5). We then generated a Nsun5 null (Nsun5–/–) mouse model to validate the human findings by defining the functions of Nsun5 in OFT morphogenesis. The OFT did not develop properly in the Nsun5 deletion embryonic heart. We found a misalignment of the aorta and septum defects caused by the delayed fusion of the membraneous ventricular spetum as an OFT development delay. This caused OFT development delay in 27 of 64 (42.2%) Nsun5–/– mice. Moreover, we also found OFT development delay in 8 of 51 (15.7%) Nsun5+/– mice. Further functional experiments showed that the loss of Nsun5 function impaired the 5-methylcytosine (m5C) modification and translation efficiency of essential cardiac genes. Nsun5 is required for normal OFT morphogenesis and it regulates the m5C modification of essential cardiac genes. Our findings suggest the involvement of NSUN5 in the pathogenesis of TOF.
Highlights
Congenital heart disease (CHD) is the most common congenital anomaly in live births (van der Bom et al, 2011)
We screened for potential mutations in the NSUN5 coding region of a cohort of 132 tetralogy of Fallot (TOF) patients by Sanger sequencing
We characterized a novel missense mutation (c.324G > T, p.A100S) in a methylase domain (Figure 1B and Supplementary Figure 3B), a nonsense mutation c.1236_1240delTGCCT (p.CL404fs∗5) in a S-adenosylmethionine-dependent methyltransferase domain (Figure 1B and Supplementary Figure 3C), and another non-sense mutation c.1370_1373delAGAA (p.KE448fs∗17) in a translational termination position (Figure 1B and Supplementary Figure 3D). These results suggest that NSUN5 might be a TOF-associated gene
Summary
Congenital heart disease (CHD) is the most common congenital anomaly in live births (van der Bom et al, 2011). NSUN5 in Outflow Tract Development outcome of TOF remains a huge health problem due to right ventricular dyssynchrony and sudden cardiac death (Valdeomillos et al, 2019). A recent study reported that developmental disorders were caused by a 7q11.23 deletion that included several genes with roles in epigenetic regulation, including methylation (Strong et al, 2015). It was reported that post-transcriptional modification is necessary for heart development. A recent study revealed that a marked excess of mutations in genes involved in the production, removal, or reading of H3K4 and H3K27 epigenetic modifications, were important for cardiac development (Zaidi et al, 2013). Whether Nsun is a candidate gene in the 7q11.23 locus deletion that results in TOF and whether its m5C modification has a role in the regulation of cardiac genes during OFT development are not known
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