Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment

In genetic disease, an accurate expression landscape of disease genes and faithful animal models can facilitate genetic diagnoses and therapeutic advances respectively. Previously, we found that variants in NOS1AP, the gene that encodes nitric oxide synthase 1 adaptor protein, cause monogenic nephrotic syndrome. Here, we determine that an intergenic splice product of NOS1AP/Nos1ap and neighboring C1orf226/Gm7694, which prevents NOS1AP from binding to nitric oxide synthase 1, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694<sup>-/-</sup> mice, whose allele exclusively disrupts the intergenic product, develop nephrotic syndrome phenotypes. In two male human subjects with nephrotic syndrome, we identify 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 generate a faithful mouse model of NOS1AP-associated monogenic nephrotic syndrome that responds to anti-proteinuric treatment.

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Nature Communications
Published
2025-11-27
DOI
https://doi.org/10.1038/s41467-025-65663-6
Primary Topic
Nitric Oxide and Endothelin Effects
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article
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article

Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment

Sergio Guerrero‐Castillo, Mohamed Shalaby, Josée Normand, Mohamed H. Al‐Hamed et al.
Nature Communications
Nitric Oxide and Endothelin Effects
article

Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment

Sergio Guerrero‐Castillo, Mohamed Shalaby, Josée Normand, Mohamed H. Al‐Hamed, Jameela A. Kari, Amar J. Majmundar, Biju Issac, Alexis C. Gomez, Björn Reusch, Ken Saida, Lea Maria Merz, Sanja Sever, Alexander Rubin, J. Paul Fawcett, Kavita Krueger, Jiansong Qi, Markus Matthias Rinschen, David Ball, Vineeta Sharma, Matthew Gordon Sampson, Daanya Salmanullah, Katharina Lemberg, Michelle T. McNulty, Fatih Demir, Bodo B. Beck, Friedhelm Hildebrandt, Qianyi Ma, A. Billing, Adrian Ranga, Florian Buerger, Victoria C. Gauntner, Sunwoo Hong, Liang Sun, Mohammed M. Saleh, Lorrin Liang
article en

Abstract

In genetic disease, an accurate expression landscape of disease genes and faithful animal models can facilitate genetic diagnoses and therapeutic advances respectively. Previously, we found that variants in NOS1AP, the gene that encodes nitric oxide synthase 1 adaptor protein, cause monogenic nephrotic syndrome. Here, we determine that an intergenic splice product of NOS1AP/Nos1ap and neighboring C1orf226/Gm7694, which prevents NOS1AP from binding to nitric oxide synthase 1, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694<sup>-/-</sup> mice, whose allele exclusively disrupts the intergenic product, develop nephrotic syndrome phenotypes. In two male human subjects with nephrotic syndrome, we identify 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 generate a faithful mouse model of NOS1AP-associated monogenic nephrotic syndrome that responds to anti-proteinuric treatment.

Nature CommunicationsVol. 16(1)
Broad Institute (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), Dalhousie University (CA), Harvard University (US), Universität Hamburg (DE), University of Cologne (DE), King Abdulaziz University (SA), Aarhus University (DK), King Faisal Specialist Hospital & Research Centre (SA), King Fahd Medical City (SA), Massachusetts General Hospital (US), University Medical Center Hamburg-Eppendorf (DE), King Abdulaziz Hospital (SA), Boston Children's Museum (US), University Hospital Cologne (DE), Leipzig University (DE)
American Society of Nephrology, Aarhus Universitet, Alport Syndrome Foundation, Rare Diseases Clinical Research Network, Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, Novo Nordisk, Novo Nordisk Fonden, National Institutes of Health, Manton Center for Orphan Disease Research, Boston Children's Hospital, Canadian Institutes of Health Research, Japan Society for the Promotion of Science, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Openalex Percentile: Top 54%
Nitric Oxide and Endothelin Effects
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