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

Florian Buerger, Daanya Salmanullah, Lorrin Liang, Victoria Gauntner, Kavita Krueger, Jiansong Qi, Josee Normand, Vineeta Sharma, Arathi Ranga, Alexander Rubin, David Ball, Sunwoo Hong, Katharina Lemberg, Ken Saida, Lea Maria Merz, Sanja Sever, Biju Issac, Qianyi Ma, Liang Sun, Anja M. Billing, Fatih Demir, Markus M. Rinschen, Björn Reusch, Bodo B. Beck, Sergio Guerrero-Castillo, Alexis C. Gomez, Michelle T. McNulty, Matthew G. Sampson, Mohamed H. Al-Hamed, Mohammed M. Saleh, Mohamed A. Shalaby, Jameela A. Kari, James P. Fawcett, Friedhelm Hildebrandt () and Amar J. Majmundar ()
Additional contact information
Florian Buerger: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Daanya Salmanullah: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Lorrin Liang: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Victoria Gauntner: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Kavita Krueger: Dalhousie University, Department of Pharmacology
Jiansong Qi: Dalhousie University, Department of Pharmacology
Josee Normand: Dalhousie University, Department of Pharmacology
Vineeta Sharma: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Arathi Ranga: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Alexander Rubin: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
David Ball: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Sunwoo Hong: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Katharina Lemberg: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Ken Saida: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Lea Maria Merz: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Sanja Sever: Harvard Medical School, Department of Medicine
Biju Issac: Boston Children’s Hospital, Research Informatics, Information Technology
Qianyi Ma: Boston Children’s Hospital, Research Informatics, Information Technology
Liang Sun: Boston Children’s Hospital, Research Informatics, Information Technology
Anja M. Billing: Aarhus University, Department of Biomedicine
Fatih Demir: Aarhus University, Department of Biomedicine
Markus M. Rinschen: University Medical Center Hamburg-Eppendorf, Hamburg Center for Kidney Health (HCKH)
Björn Reusch: University of Cologne, Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine
Bodo B. Beck: University of Cologne, Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine
Sergio Guerrero-Castillo: University Medical Center Hamburg-Eppendorf, University Children’s Hospital
Alexis C. Gomez: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Michelle T. McNulty: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Matthew G. Sampson: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Mohamed H. Al-Hamed: King Faisal Specialist Hospital & Research Centre, Clinical Genomics Department, Centre for Genomic Medicine
Mohammed M. Saleh: King Fahad Medical City, Section of Medical Genetics, Children Specialist Hospital
Mohamed A. Shalaby: King Abdulaziz University Hospital, Pediatric Nephrology Centre of Excellence, Faculty of Medicine
Jameela A. Kari: King Abdulaziz University Hospital, Pediatric Nephrology Centre of Excellence, Faculty of Medicine
James P. Fawcett: Dalhousie University, Department of Pharmacology
Friedhelm Hildebrandt: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital
Amar J. Majmundar: Harvard Medical School, Department of Pediatrics, Boston Children’s Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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−/− 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65663-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65663-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65663-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().