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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.

Original publication




Journal article


Mamm Genome

Publication Date





404 - 415


Abnormalities, Multiple, Amino Acid Sequence, Animals, Cardiovascular System, Cells, Cultured, DNA Mutational Analysis, Female, GTPase-Activating Proteins, Gene Expression Profiling, Genetic Association Studies, Heart Defects, Congenital, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Molecular Sequence Annotation, Molecular Sequence Data, Myocardium, Nuclear Proteins, Phenotype, Polymorphism, Single Nucleotide, Promoter Regions, Genetic