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Abstract: FR-PO785

Recessive Mutations in TLN1, PAX, or ARHGEF17 Are Potential Novel Causes of Nephrotic Syndrome in Humans

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Ashraf, Shazia, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Mao, Youying, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Schneider, Ronen, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Kari, Jameela Abdulaziz, King abdulaziz University, Jeddah, Saudi Arabia
  • Soliman, Neveen, Cairo University, Cairo, Egypt
  • Hildebrandt, Friedhelm, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Steroid resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage kidney disease. Although more than 60 single-gene causes of SRNS are known, a large proportion remains unexplained. Recently, we identified mutations in MAGI2, TNS2, DLC1 and CDK20 genes as novel causes of NS (Ashraf Nat Commun 17:1960, 2018). Study of these proteins provided new insights into the pathogenesis of NS, linking into small GTPase ‘RhoA’ function.

Methods

We performed whole exome sequencing (WES) to identify novel monogenic causes of NS in >1,000 individuals with NS.

Results

We identified 4 different recessive mutations in 3 different genes TLN1 (Talin1), PAX (Paxillin) and ARHGEF17 (Tem4) in 4 unrelated families with NS. Specifically, in two individuals with NS, we identified a highly conserved homozygous TLN1 mutation (family B3328, I1989del), or compound heterozygous mutations (family A3788, M79V and S1164W) in TLN1, which is known to interact with integrins and actin, and plays a role in activating integrins via its F3 N-terminal domain at focal adhesions. Knockout mice of Tln1 have been previously shown to develop severe proteinuria, foot process effacement, and kidney failure. Additionally, we also discovered recessive homozygous mutations in PAX (family A3995, Y281H, conserved to D. rerio) and ARHGEF17 (family A3658, V1883M, conserved to C. elegans). Interestingly, TLN1, PAX and ARHGEF17 are highly expressed in podocytes and directly interact with TNS2 and DLC1, which are both known to cause NS, if mutated. Talin1 and Tem4 are also known to specifically affect RhoA function in vitro.

Conclusion

We have identified mutations of TLN1, PAX and ARHGEF17 as novel causes of NS. Our findings confirm that Rho-like small GTPase signaling is part of NS pathogenesis.

Funding

  • NIDDK Support