ABSTRACT
In 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 in NOS1AP, encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of NOS1AP/Nos1ap and neighboring C1orf226/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 causative NOS1AP splice 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 of NOS1AP-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.
Competing Interest Statement
F.H. is a co-founder of Goldfinch Biopharma Inc. A.J.M. is a consultant for Judo, Inc. The other authors declare that they have no competing financial interests. No part of this manuscript has been previously published.
Funding Statement
A.J.M. was supported by the NIH (5K12HD052896-13, 1K08DK125768-01A1), American Society of Nephrology (Norman Siegel Research Scholar Career Grant 81542), Manton Center for Orphan Disease Research (Junior Faculty Award), and Boston Childrens Hospital OFD/BTREC/CTREC Faculty Career Development Fellowship. F.H. is the William E. Harmon Professor of Pediatrics and has grant support from the National Institutes of Health (5R01DK076683-13). L.M., K.L. and F.B. were supported by the German Research Foundation (ME 5722/1-1, 456136540, 499462148, 461126211 and 404527522 respectively). This study was further supported by a grant from the American Society of Nephrology to F.B. (Carl W. Gottschalk Research Scholar). F.B. was further supported by the Else Kroener-Fresenius-Stiftung (iPRIME Clinician Scientist Forschungskolleg - 2021_EKFK.15, UKE, Hamburg, Germany). K.S. was funded by the JSPS Overseas Research Fellowships (No. 202260295). M.G.S. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119380 and RC2DK122397) and the Pura Vida Kidney Foundation. A.C.G. is supported by NIH T32-DK007726. The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support is provided by the University of Michigan, NephCure, Alport Syndrome Foundation, and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC), funded by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) under U2CTR002818.
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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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Institutional Review Boards of the University of Michigan and Boston Childrens Hospital and King Faisal Specialist Hospital and Research Centre gave ethical approval for this work.
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Data Availability
All data produced in the present study are either already contained in the manuscript or remaining data available upon reasonable request to the authors.