Kidney Week

Abstract: SA-PO563

Mutations of GAPVD1 and ANKFY1 Are Novel Causes of Nephrotic Syndrome

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Hermle, Tobias F., Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Tobias F. Hermle,

• Schneider, Ronen, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Ronen Schneider,

• Schapiro, David, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

David Schapiro,

• El desoky, Sherif Mohamed, King Abdul Aziz University Hospital, Jeddah, Saudi Arabia

Sherif Mohamed El desoky,

• Kari, Jameela Abdulaziz, King Abdul Aziz University Hospital, Jeddah, Saudi Arabia

Jameela Abdulaziz Kari,

• Braun, Daniela A., Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Daniela A. Braun,

• Hildebrandt, Friedhelm, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Steroid resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal disease within the first 3 decades of life. The discovery of more than 50 different monogenic causes has helped to elucidate the pathogenesis of SRNS.

Methods

To identify novel monogenic causes of SRNS we performed homozygosity mapping and whole exome sequencing (WES) in a worldwide cohort of ~600 individuals with nephrotic syndrome. Co-immunoprecipitation using HEK cells was employed to analyze protein interaction.

Results

By WES we identified two homozygous missense mutations of GAPVD1 (c.1240C>G, p.L414V and c.2810G>A, p.R937Q) in two patients from unrelated families with early-onset nephrotic syndrome. Both mutated amino acids are conserved to C. intestinalis. One patient did not respond to steroids while the other showed the unusual combination of congenital nephrotic syndrome and spontaneous remission. This has previously been observed in few alleles of NPHS1. The histology in both cases was characterized by mesangial hypercellularity while electron microscopy revealed podocyte foot process effacement. GAPVD1 is a known regulator of endosomal trafficking and interacts with RAB5. GAPVD1 harbors both, a GTPase activating and an inactivating domain.
We further identified a mutation of ANKFY1 (c.284G>T, p.R95L, conserved to D. melanogaster) in a patient with SRNS and FSGS with an affected sibling sharing the mutation. ANKFY1 is also an interaction partner of RAB5 and serves as a RAB5-effector.
Western blotting revealed expression of GAPVD1 and ANKFY1 in a human podocyte cell line. Using co-immunoprecipation we observed physical interaction between both proteins. We further found interaction of GAPVD1 and the slit diaphragm protein NPHS1. Mapping experiments suggest that both functional domains of GAPVD1 bind to NPHS1.

Conclusion

We discover mutations of GAPVD1 and ANKFY1 as novel monogenic causes of nephrotic syndrome. Interestingly, both proteins interact with each other and RAB5. GAPVD1 further interacts with NPHS1, mutations in which cause SRNS.

Funding

• Other NIH Support