Kidney Week

Abstract: FR-PO1007

Mutations of NEK3, PREX1, or TIAM1 Are Novel Causes of Nephrotic Syndrome

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Ashraf, Shazia, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Shazia Ashraf,

• Gee, Heon Yung, Yonsei University College of Medicine, Seoul, Korea (the Republic of)

Heon Yung Gee,

• Mao, Youying, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Youying Mao,

• Jobst-Schwan, Tilman, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Tilman Jobst-Schwan,

• Shril, Shirlee, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Shirlee Shril,

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

Friedhelm Hildebrandt,

Background

Nephrotic syndrome (NS) is a heterogeneous group of disorders characterized by gross proteinuria with hypoalbuminemia and edema. The identification of >55 single-gene causes provided new insights into the pathogenesis of NS, linking Rho-like small GTPases to podocyte 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 NEK3, PREX1 and TIAM1 in 4 unrelated families with NS. Specifically, in a family of two siblings (F754) with steroid-sensitive NS, we identified a homozygous truncating mutation, N209Kfs*21 in NEK3 (NIMA Related Kinase 3), which is known to be activated by prolactin stimulation, leading to phosphorylation of the GEF-VAV2 and thereby activation of the Rac1-GTPase. Accordingly, by coimmunoprecipitation, we demonstrated that NEK3 interacts with VAV1, VAV2 and EDH2 proteins. The mutated NEK3 protein showed stronger binding affinity with VAV1 but abrogated the interaction with EHD2. Coimmunofluorescence staining of NEK3 in developing rat kidney sections (P1) showed that NEK3 localizes to the cytoplasm of podocytes. Additionally, we discovered mutations in PREX1 (family F1070, M1546T [Hom], conserved to D. rerio) and TIAM1 (family F1287, R23C [het] and A163V [het], both conserved to D. rerio; family F1, p.R23C [Hom]). We thereby identified PREX1 and TIAM1 as two novel GEFs for Rac1 that are relevant for podocyte function.

Conclusion

We have identified mutations of NEK3, PREX1 and TIAM1 as novel causes of NS. Our findings confirm that Rho-like small GTPase signaling in podocytes can cause NS.

Funding

• Other NIH Support