Recessive variants in the intergenicNOS1AP-C1orf226locus cause monogenic kidney disease responsive to anti-proteinuric treatment

Abstract

ABSTRACTIn genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants inNOS1AP, encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of NOS1AP/Nos1apand neighboringC1orf226/Gm7694, which precludes NOS1 binding, is the predominant isoform in mammalian kidney transcriptional and proteomic data.Gm7694-/-mice, whose allele exclusively disrupts the intergenic product, developed NS phenotypes. In two human NS subjects, we identified causativeNOS1APsplice variants, including one predicted to abrogate intergenic splicing but initially misclassified as benign based on the canonical transcript. Finally, by modifying genetic background, we generated a faithful mouse model ofNOS1AP-associated NS, which responded to anti-proteinuric treatment. This study highlights the importance of intergenic splicing and a potential treatment avenue in a mendelian disorder.