PXD058044

PXD058044 is an original dataset announced via ProteomeXchange.

Title	Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-12-08
AnnouncementXML	Submission_2025-12-07_16:59:47.820.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Anja Billing
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-19 05:33:49	ID requested
⏵ 1	2025-12-07 16:59:48	announced

10.1038/s41467-025-65663-6;

Buerger F, Salmanullah D, Liang L, Gauntner V, Krueger K, Qi J, Normand J, Sharma V, Ranga A, Rubin A, Ball D, Hong S, Lemberg K, Saida K, Merz LM, Sever S, Issac B, Ma Q, Sun L, Billing AM, Demir F, Rinschen MM, Reusch B, Beck BB, Guerrero-Castillo S, Gomez AC, McNulty MT, Sampson MG, Al-Hamed MH, Saleh MM, Shalaby MA, Kari JA, Fawcett JP, Hildebrandt F, Majmundar AJ, Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment. Nat Commun, 16(1):10654(2025) [pubmed]

submitter keyword: mice, kidney,newborn

Markus M Rinschen, MD
contact affiliation	Department of Biomedicine, Aarhus University, Aarhus, Denmark
contact email	rinschen@biomed.au.dk
lab head
Anja Billing
contact affiliation	Aarhus University
contact email	anja.billing@biomed.au.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058044
     1. Label: PRIDE project
     2. Name: Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment