Tbc1d8b, a GTPase-activating protein, is involved in endocytic and recycling pathways, likely through its interaction with RAB11, a key protein in vesicular recycling [1,2,3]. It also interacts with nephrin, a podocyte slit diaphragm protein, and plays a role in endosomal maturation and degradation [3]. Its functions are crucial for podocyte biology and are evolutionarily conserved [3].

Mutations in Tbc1d8b have been identified as monogenic causes of steroid-resistant nephrotic syndrome (SRNS) [1,2]. In zebrafish, knockdown and knockout of the Tbc1d8b ortholog induced proteinuria, a phenotype rescued by human Tbc1d8b mRNA but not by mutated mRNAs, indicating its importance in maintaining normal renal function [2]. In Drosophila, deletion of Tbc1d8b led to nephrin mislocalization, similar to the phenotype in patients with isolated nephrotic syndrome [3].

In conclusion, Tbc1d8b is essential for nephrin trafficking, with its loss-of-function mutations contributing to the pathogenesis of nephrotic syndrome. Studies using gene knockout models in zebrafish and Drosophila have been instrumental in revealing its role in maintaining normal podocyte function and renal health [2,3].

References:

1. Kampf, Lina L, Schneider, Ronen, Gerstner, Lea, Hildebrandt, Friedhelm, Hermle, Tobias. 2019. TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome. In Journal of the American Society of Nephrology : JASN, 30, 2338-2353. doi:10.1681/ASN.2019040414. https://pubmed.ncbi.nlm.nih.gov/31732614/

2. Dorval, Guillaume, Kuzmuk, Valeryia, Gribouval, Olivier, Saleem, Moin A, Antignac, Corinne. 2019. TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways. In American journal of human genetics, 104, 348-355. doi:10.1016/j.ajhg.2018.12.016. https://pubmed.ncbi.nlm.nih.gov/30661770/

3. Milosavljevic, Julian, Lempicki, Camille, Lang, Konrad, Pollak, Martin R, Hermle, Tobias. 2022. Nephrotic Syndrome Gene TBC1D8B Is Required for Endosomal Maturation and Nephrin Endocytosis in Drosophila. In Journal of the American Society of Nephrology : JASN, 33, 2174-2193. doi:10.1681/ASN.2022030275. https://pubmed.ncbi.nlm.nih.gov/36137753/