Neuroprogenitor Cells From Patients With TBCK Encephalopathy Suggest Deregulation of Early Secretory Vesicle Transport.

Danielle De Paula Moreira,Débora Romeo Bertola,Elaine Cristina Zachi,Rafaela Regina Cardoso,Merari De Fátima Ramires Ferrari,Marcelo Andrade De Lima,André Luiz Teles E Silva,Maria Cecília Zorél Meneghetti,Elisa Varella-Branco,Naila Cristina Vilaça Lourenço,Helena Bonciani Nader,Karina De Souza Weinmann,Maria Rita Passos-Bueno,Gerson Shigeru Kobayashi,Mariana Fogo,Karina Griesi-Oliveira,Andrea Laurato Sertié,Angela May Suzuki

doi:10.3389/fncel.2021.803302

Abstract

Biallelic pathogenic variants in TBCK cause encephaloneuropathy, infantile hypotonia with psychomotor retardation, and characteristic facies 3 (IHPRF3). The molecular mechanisms underlying its neuronal phenotype are largely unexplored. In this study, we reported two sisters, who harbored biallelic variants in TBCK and met diagnostic criteria for IHPRF3. We provided evidence that TBCK may play an important role in the early secretory pathway in neuroprogenitor cells (iNPC) differentiated from induced pluripotent stem cells (iPSC). Lack of functional TBCK protein in iNPC is associated with impaired endoplasmic reticulum-to-Golgi vesicle transport and autophagosome biogenesis, as well as altered cell cycle progression and severe impairment in the capacity of migration. Alteration in these processes, which are crucial for neurogenesis, neuronal migration, and cytoarchitecture organization, may represent an important causative mechanism of both neurodevelopmental and neurodegenerative phenotypes observed in IHPRF3. Whether reduced mechanistic target of rapamycin (mTOR) signaling is secondary to impaired TBCK function over other secretory transport regulators still needs further investigation.

Highlights

Genomic high throughput studies in cohorts of individuals with neurodevelopmental disorders, involving autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID), have recognized several novel rare genetic syndromes
We examined the effect of lack of functional TBCK protein over clathrin, RAB5A, and STAM expression in in neuroprogenitor cells (iNPC) grown as neurospheres (3D model system)
We described two sisters who were referred to the CEGH-CEL at the age of 3 and 6 years due to suspected ASD

Summary

Introduction

Genomic high throughput studies in cohorts of individuals with neurodevelopmental disorders, involving autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID), have recognized several novel rare genetic syndromes. Biallelic pathogenic variants in TBCK (TBC1 domain containing kinase) have been shown to cause infantile hypotonia with. The number of reported cases is still limited to about 40 cases, and the description of novel cases can contribute to a better characterization of the spectrum of clinical variability of this syndrome. TBCK has been proposed to act on cell proliferation and autophagy through the mechanistic target of rapamycin (mTOR) signaling pathway in non-neural studies (Liu et al, 2013; Ortiz-González et al, 2018). Biallelic loss-of-function variants in TBCK are associated with several neural clinical phenotypes, functional studies of TBCK in neural cells are still lacking

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Conclusion