Kidney Week

Abstract: FR-PO685

Recessive Variants in the Intergenic NOS1AP-C1orf226 Locus Cause Monogenic Kidney Disease

Session Information

• Pediatric Nephrology - 1
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

• 1900 Pediatric Nephrology

Authors

• Buerger, Florian, Boston Children's Hospital, Boston, United States

Florian Buerger, MD, PhD

• Gauntner, Victoria C., Boston Children's Hospital, Boston, Massachusetts, United States

Victoria C. Gauntner

• Sharma, Vineeta, Boston Children's Hospital, Boston, Massachusetts, United States

Vineeta Sharma, PhD

• Guerrero Castillo, Sergio, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Sergio Guerrero Castillo, PhD

• Sun, Liang, Boston Children's Hospital, Boston, Massachusetts, United States

Liang Sun

• Gomez, Alexis C., Boston Children's Hospital, Boston, Massachusetts, United States

Alexis C. Gomez, MD

• Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States

Michelle Mcnulty, MS

• Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

• Al-hamed, Mohamed, King Fahad Medical City, Riyadh, Riyadh, Saudi Arabia

Mohamed Al-hamed

• Fawcett, James P., Dalhousie University, Halifax, Nova Scotia, Canada

James P. Fawcett, PhD

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

• Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States

Amar J. Majmundar, MD, PhD

Background

An accurate expression landscape of disease genes is crucial to enable precise genetic diagnoses. Canonical NOS1AP, encoding nitric oxide synthase 1 (NOS1) adaptor protein, is known to regulate hippocampal neuronal functions through C-terminal interactions with the enzyme NOS1 (Jaffrey Neuron 1998; Zhu Nat Med 2014). We previously discovered that N-terminal variants in NOS1AP cause monogenic nephrotic syndrome (NS) in humans and mice (Majmundar Sci Adv 2021). However, the role of the NOS1AP C-terminus in NS pathogenesis was unclear.

Methods

Transcriptomics and proteomics data of human and murine kidney samples were evaluated. Exome sequencing was performed in human NS subjects. Mouse models altering the Nos1ap locus were evaluated for features of NS.

Results

We, here, detected intergenic splice products of NOS1AP/Nos1ap and the neighboring open reading frame C1orf226/Gm7694 as the predominant isoform in both human and mouse kidney tissue in contrast to brain tissue. In this isoform, the canonical C-terminal NOS1-binding domain is replaced by C1orf226 or Gm7694, respectively. In line with our previously published Nos1ap-deficient mice, exclusive disruption of the intergenic product in Gm7694^-/- mice similarly resulted in NS features including albuminuria, podocyte foot process effacement, and glomerular basement membrane thickening. We, next, evaluated whether recessive variants exclusively impacting the intergenic splice form can be detected in NS patients. For this, we reanalyzed NS exome sequencing data and thereby identified a likely pathogenic NOS1AP-C1orf226 essential splice site variant (c.1258+1G>C) in a patient with congenital NS. Of note, this variant was initially misclassified as benign due to annotation based on the canonical transcript (c.1259G>C, p.G420A).

Conclusion

Mendelian variants impacting an intergenic product in the NOS1AP-C1orf226 locus cause NS, suggesting that, unlike in the brain, NOS1AP functions in the kidney through NOS1-independent mechanisms. Moreover, this highlights the importance of understanding tissue-specific splicing to facilitate discovery and clinical diagnosis of Mendelian disorders.

Funding

• NIDDK Support