Abstract: SA-PO573
TBC1D8B Mutations Are a Novel Cause 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
- Schneider, Ronen, Boston Childrens Hospital, Boston, Massachusetts, United States
- Hermle, Tobias F., Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States
- Schapiro, David, Boston Children's Hospital, Brookline, Massachusetts, United States
- Berdeli, Afig, Ege University Medical Faculty, Izmir, Turkey
- Loza, Reyner F, Cayetano Heredia Hospital, Los Olivos, Peru
- Braun, Daniela A., Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Brookline, Massachusetts, United States
Background
Nephrotic Syndrome (NS) is the second most frequent cause of end-stage renal disease in the first 3 decades of life. RAB proteins are regulators of endocytosis, which is an important feature of podocyte function. Identification of 50 monogenic genes that if mutated cause NS, has rendered first insights into disease mechanisms of NS. To date no monogenic mutations affecting RAB proteins or related proteins have been implicated in the pathomechanism of NS.
Methods
To identify novel monogenic causes of NS we combined homozygosity mapping with whole exome sequencing (WES) in a worldwide cohort of ~600 individuals with NS.
Results
In patient B931 with steroid resistant NS (SRNS) and FSGS, who presented at the age of 9 years, we detected a hemizygous mutation in the X-chromosomal gene TBC1D8B (c.2338A>T; p.Thr780Ser). Thr780 is conserved since D. Rerio.
In patient A2563 who presented with steroid sensitive NS (SSNS) at the age of 7 years, and had minimal change disease on renal biopsy, we detected a hemizygous TBC1D8B mutation (c.190C>T; p.Arg64Cys). Arg64 is highly conserved since S. Cerevisiae. Both TBC1D8B mutations are predicted to be disease causing by SIFT, MutaTaster and PolyPhen2 software programs. Both variants are not present hemizygously in the ExAC database.
The yeast orthologue for TBC1D8B, Msb3, has GTPase Activating Protein (GAP) activity for RAB proteins, which play a role in the endocytic pathway (Lachmann, Mol Biol Cell, 23: 2516, 2012). By Western blot and gene specific siRNA knockdown we show that TBC1D8B is expressed in a human podocyte cell line. By Co-IP studies we show that RAB5, a key regulator of endocytic trafficking, interacts with TBC1D8B protein when overexpressed in human HEK cells. TBC1D8B also interacts with endogenous RAB5. In human podocytes TBC1D8B localizes to vesicles but does not co-localize with RAB5, RAB7, or RAB11.
Conclusion
We here identify recessive mutations of TBC1D8B as a likely novel monogenic cause of nephrotic syndrome. Interaction with RAB5 without co-localization of both proteins suggests that another RAB protein may be the primary target of TBC1D8B. Further functional studies will shed light on the pathomechanism of TBC1D8B loss-of-function in NS.
Funding
- Other NIH Support