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Kidney Week

Abstract: FR-PO782

PLXNB2 Mutations Are a Likely Cause of Congenital Anomalies of the Kidneys and Urinary Tract in Humans and Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Dai, Rufeng, Boston Children's Hospital, Boston, United States
  • Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Wu, Chen-Han Wilfred, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kause, Franziska, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Kolvenbach, Caroline M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Worzfeld, Thomas, University of Marburg, Marburg, Germany
  • Höß, Carsten, Institute of Pharmacology, BPC, University of Marburg, Marburg, Germany
  • Zhang, Xuewu, University of Southwestern Medical Center, Dallas, Texas, United States
  • Hoefele, Julia, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
  • Riedhammer, Korbinian M., Technical University of Munich, Munich, Germany
  • Stajic, Natasa, Institute for Mother and Child Health Care, Belgrade, Serbia, Belgrade, Serbia
  • Rao, Jia, Children's Hospital of Fudan University, Shanghai, China
  • Shen, Qian, Children's Hospital of Fudan University, Shanghai, China
  • Xu, Hong, Children's Hospital of Fudan University, Shanghai, China
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of end-stage renal disease in children, but the genetic causes of CAKUT remains largely elusive. Gene mutant mouse models are important research tools for human CAKUT, to date, 185 genes that if mutated causes murine CAKUT phenotypes is in the MGI database (http://www.informatics.jax.org). Most of them could also be a potential cause of CAKUT in humans.

Methods

To identify novel monogenic causes of CAKUT in humans, we performed whole exome sequencing (WES) in a worldwide cohort of 703 individuals with CAKUT. Based on the mode of inheritance in mice and pLI scores (Loss of function intolerant) in the ExAC database for the 185 murine CAKUT genes, we screened for variants in these genes in our CAKUT WES data to discover novel human candidate CAKUT genes. Functional studies were carried out to verify the pathogenesis of variants in these candidate genes.

Results

We identified 6 different heterozygous mutations in PLXNB2 in 7 individuals from 6 unrelated families, one heterozygous mutation occurred de novo. Affected individuals exhibited a broad spectrum of CAKUT phenotypes, while, 77% of individuals exhibited syndromic features. With functional studies, we found mutations in PLXNB2 destabilized the PLXNB2 protein, damaged the synthetic PLXNB2 protein transport, weakened the binding ability of the PLXNB2 protein to its receptor, Semaphorin 4, and influenced the cells migration and the activity of CDC42 and Ras in cells.

Conclusion

Our results support that mutations in PLXNB2 are a novel cause of human syndromic CAKUT through defective cell migration via influencing the activity of CDC42-Ras or through defective Semaphorin-Plexin signaling.