Mutations in TBC1D8B affect Rab11-activity and cause nephrotic syndrome

Abstract: Podocytes, as part of the three-layered glomerular filter, build slit diaphragms between adjacent cells mainly consisting of the proteins nephrin and NEPH1. In case of a filtration deficiency, patients develop nephrotic syndrome (NS), a common malady among children. In approx. a quarter of the children with NS resistant to steroid-treatment (SRNS), a single-point mutation can be identified as the monogenic cause of their disease. By whole exome sequencing novel missense mutations in the gene TBC1D8B were found in five patients with genetic SRNS. Evolutionary conservation of the respective amino acids and a low allele frequency in a healthy control population suggested a pathological relevance of the novel mutations. Other members of the TBC-protein family have been shown to function as GTPase-activating proteins (GAP) for specific Rab proteins. However, the function of TBC1D8B and its role in the pathogenesis of NS were mostly unknown.
Aim of this work was to analyse the function of TBC1D8B, evaluate its potential role as a monogenic cause of NS and to explore possible pathomechanisms.
In vitro studies showed that TBC1D8B specifically interacts with GTP-bound Rab11. Silencing TBC1D8B disinhibited Rab11-dependent processes. The results indicate TBC1D8B functioning as a GAP for Rab11. TBC1D8B also interacted and colocalised with nephrin, which is subject to vesicular trafficking. Introducing the patients’ mutations weakened the interaction with Rab11 and nephrin. The data was complemented by studies in podocyte-like Drosophila nephrocytes. Silencing fly Tbc1d8b (CG7324) caused mistrafficking of fly nephrin (Sns) and NEPH1 (Kirre). Nephrocyte function, measured with the FITC albumin uptake, was also decreased showing functional consequences due to the loss of Tbc1d8b.
Taken together, TBC1D8B was identified as a novel monogenic cause of NS. The functional analysis of TBC1D8B implicates its role as a GAP for Rab11 while also interacting with nephrin. The results suggest dysregulation of Rab11-dependent vesicular trafficking of nephrin upon TBC1D8B mutations which provides new insights in both, podocyte biology and SRNS-pathogenesis, and might reveal potential therapeutic targets in the future

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2023

Klassifikation und Themen

• Schlagwort: Taufliege ; Nierenkrankheit ; Pathophysiologie ; Podocyte ; Nephrotisches Syndrom ; Endocytose ; Nierenkrankheit ; Nephrologie

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Kampf, Lina L.
• Beteiligte Personen und Organisationen: Hermle, Tobias Franz ; Walz, Gerd ; Walz, Gerd ; Simons, Matias ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät ; Klinik für Innere Medizin IV. Freiburg im Breisgau ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Weitere Informationen

• DOI: 10.6094/UNIFR/237169
• URN: urn:nbn:de:bsz:25-freidok-2371690
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:43 MEZ