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Abstract: SA-PO578

X-Linked Recessive Variants in X-Prolyl Aminopeptidase 2 (XPNPEP2) as a Potential New Cause of Nephrotic Syndrome

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mansour, Bshara, Boston Children's Hospital, Boston, Massachusetts, United States
  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
  • Lemberg, Katharina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Nicolas Frank, Camille H., Boston Children's Hospital, Boston, Massachusetts, United States
  • Yousef, Kirollos, Boston Children's Hospital, Boston, Massachusetts, United States
  • Connaughton, Dervla M., London Health Sciences Centre, London, Ontario, Canada
  • Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
  • Bakkaloglu, Sevcan A., Gazi Universitesi, Ankara, Ankara, Turkey
  • El desoky, Sherif Mohamed, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • Kari, Jameela Abdulaziz, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease in children and young adults. Major insights into its pathogenesis came from the discovery of ~68 monogenic causes, contributing to ~11-30% of SRNS with onset <25 years of age. However, a significant proportion remains without a genetic diagnosis.

Methods

To identify novel potential monogenic causes of SRNS, we performed whole-exome sequencing (WES) in a worldwide cohort of individuals with SRNS from 1,285 different families. We evaluated potential pathogenicity of bi-allelic hemizygous genetic variants by in-silico prediction scores, evolutionary conservation, and allele frequency in public genome sequencing databases.

Results

We discovered, 3 different X-linked recessive, likely deleterious variants in XPNPEP2 (X-Prolyl Aminopeptidase 2) in unrelated male individuals. Individual A4966_21 had missense variant: c.346C>T, p.(Arg116Cys), which changes an arginine residue as part of a highly conserved DXRY motif that is important for the enzyme activity. This variant is deemed as likely disease-causing by SIFT, MutTaster, and PolyPhen2 prediction programs. Individual A222_21 had a nonsense variant c.670C>T, p.(Arg224*). Individual D_10382_21 had an obligatory splice variant c.1107+1G>A. The ages of SRNS onset were 3, 15, and 2-year-old, respectively. All variants were absent hemizygously from the gnomAD database. No extra-renal manifestations were reported. Upon renal biopsy, individuals A4966_21 and D_10382_21 both showed focal segmental glomerulosclerosis, and A222_21 showed membranoproliferative glomerulonephritis.
XPNPEP2 encodes a membrane-bound isoform of aminopeptidase P (APP2), a widely distributed hydrolase that cleaves N-terminal imido bonds. One of the substrates for APP2 is Bradykinin (BK). We consider XPNPEP2 a candidate gene for SRNS/FSGS because BK has been shown to play a role in the pathogenesis of FSGS, operating through B1 receptor signaling in a mouse model (Pereira Kidney Int. 79:1217, 2011).

Conclusion

By WES, we identify X-linked recessive variants in the gene XPNPEP2 in 3 affected individuals, as a potential novel monogenic cause of SRNS.

Funding

  • Other NIH Support