Nprl3 is required for normal development of the cardiovascular system
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C16orf35 is a conserved and widely expressed gene lying adjacent to the human α-globin cluster in all vertebrate species. In-depth sequence analysis shows that C16orf35 (now called NPRL3) is an orthologue of the yeast gene Npr3 (nitrogen permease regulator 3) and, furthermore, is a paralogue of its protein partner Npr2. The yeast Npr2/3 dimeric protein complex senses amino acid starvation and appropriately adjusts cell metabolism via the TOR pathway. Here we have analysed a mouse model in which expression of Nprl3 has been abolished using homologous recombination. The predominant effect on RNA expression appears to involve genes that regulate protein synthesis and cell cycle, consistent with perturbation of the mTOR pathway. Embryos homozygous for this mutation die towards the end of gestation with a range of cardiovascular defects, including outflow tract abnormalities and ventriculoseptal defects consistent with previous observations, showing that perturbation of the mTOR pathway may affect development of the myocardium. NPRL3 is a candidate gene for harbouring mutations in individuals with developmental abnormalities of the cardiovascular system.
KeywordsGene Ontology Ventricular Septal Defect Ventricular Septal Defect mTOR Pathway Erythroid Cell
This work was supported by Marie Curie RTN EUrythron (MRTN-CT-2004-005499 to MSK), European Molecular Biology Organisation (ALT 325-2008 to LSP), Medical Research Council [Chris P. Ponting (C.P.P.) laboratory and Douglas R. Higgs (D.R.H.) laboratory], and the National Institute of Health Biomedical Research Centre Programme (D.R.H.) laboratory. We thank Dr. Taavi Neklesa for critically reading the manuscript. Thanks to Liz Ormondroyd from the Department of Cardiovascular Medicine (John Radcliffe Hospital, Oxford, UK) for collecting patients for the study. We also thank Pik-Shan Li, Christina Rode, and Sue Butler for assistance with transgenic lines production, breeding, and genotyping. We thank the patients for participation in this study.
Conflict of interest
The authors have no conflicts of interests to declare.
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