# Mutations in TBC1D8B as a potential new cause of nephrotic syndrome

> **NIH NIH F32** · BOSTON CHILDREN'S HOSPITAL · 2020 · $75,858

## Abstract

PROJECT SUMMARY
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 m...

## Key facts

- **NIH application ID:** 9949374
- **Project number:** 5F32DK122766-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Ana Claudia Onuchic-Whitford
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $75,858
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949374

## Citation

> US National Institutes of Health, RePORTER application 9949374, Mutations in TBC1D8B as a potential new cause of nephrotic syndrome (5F32DK122766-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9949374. Licensed CC0.

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