Mutations in TBC1D8B as a potential new cause of nephrotic syndrome Nephrotic syndrome (NS) is the second most common cause of chronic kidney disease before 25 years of age. Focal segmental glomerulosclerosis (FSGS) is a frequent histological manifestation of steroid-resistant nephrotic syndrome (SRNS), in which mechanisms of disease are poorly understood. Effective treatment options for SRNS are rare, ultimately requiring dialysis or transplantation. Over the past several years, the development of next-generation sequencing allowed the identification of ~55 monogenic causes of SRNS, revealing novel pathways involved in this disease. Such fundamental insights resulted in definitive molecular genetic diagnoses, discovery of therapies for specific mutations, and monitoring for extra-renal manifestations correlated with certain genotypes. Genetic causes of NS have been increasingly recognized in both pediatric and adult populations. The etiology of SRNS, an enigma for many years, went through a paradigm shift with the identification of single-gene causes of NS. This led to the fascinating discovery that most of the encoded proteins converge on signaling pathways and/or structural components of the podocyte, including slit diaphragm, actin cytoskeleton and adhesion proteins, nuclear transcription factors and COQ10 biosynthesis components. In recent years, an additional mechanism has emerged as a key regulator of podocyte function: the endocytic pathway. Components of the slit diaphragm are subject to tightly coordinated endocytosis. Knockout of dynamin 1 and 2, proteins involved in clathrin-mediated endocytosis, resulted in FSGS in mice. Mutations in MYO1E, CD2AP and GAPVD1, important regulators of endocytosis, cause NS. GAPVD1 interacts with RAB5, part of a family of RAB GTPases, which orchestrate intracellular trafficking by controlling endocytic vesicle formation, transport, docking and fusion. In my mentor?s cohort of patients with NS, two individuals were found to have different hemizygous mutations in the X-chromosomal gene TBC1D8B. Both mutations are expected to be disease-causing by pathogenicity prediction algorithms, and are extremely rare or not present in large genetic databases. TBC1D8B is part of a family of Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins, which facilitate inactivation of RAB GTPases. Preliminary studies from my mentor?s lab reveal that TBC1D8B is present in a human podocyte cell line in a vesicular staining pattern, but does not colocalize with RAB4, 5 or 11. This suggests that TBC1D8B is involved in endocytic regulation and constitutes a potential novel monogenic cause of NS, but further functional characterization of TBC1D8B is required to determine its underlying role in the pathogenesis of this disease. I will therefore pursue the following specific aims: (SA1) Characterize the effects of TBC1D8B mutations on the endocytic pathway to delineate the related disease mechanisms of NS. (SA2) Evaluate whole-exome sequencing (WES) data from 1200 families with NS for mutations in candidate genes, to identify additional components of the endocytic disease pathway of NS.

Public Health Relevance

Nephrotic syndrome (NS), which often manifests histologically as focal segmental glomerulosclerosis, is the second most common cause of chronic kidney disease before 25 years of age. The identification of monogenic causes of NS led to the discovery that most of the encoded proteins converge on signaling pathways and structural components of the podocyte, with endocytosis recently found to be among the implicated pathways. In a large cohort of families with NS, mutations were identified in the gene TBC1D8B, part of a family of RAB- specific GTPase-activating proteins involved in endocytic regulation, thereby constituting a potential novel monogenic cause of NS.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Maric-Bilkan, Christine
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Boston Children's Hospital
United States
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