Related Experiment Video

Updated: Feb 16, 2026

Construction of Homozygous Mutants of Migratory Locust Using CRISPR/Cas9 Technology
10:07

Construction of Homozygous Mutants of Migratory Locust Using CRISPR/Cas9 Technology

Published on: March 16, 2022

2.7K

Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy

Xilma R Ortiz-González1,2,3, Jesus A Tintos-Hernández1,3,4, Kierstin Keller3,4

  • 1Department of Pediatrics, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA.

Annals of Neurology
|December 29, 2017
PubMed
Abstract

Insights

Mutations in TBCK cause TBCK-encephaloneuronopathy (TBCKE), a neurodegenerative disorder. This study found that activating mTORC1 may improve autophagic-lysosomal dysfunction in TBCKE patients.

Area of Science:

  • Genetics and Neurology
  • Molecular Biology
  • Metabolic Disorders

Background:

  • Autosomal-recessive mutations in TBCK gene are linked to intellectual disability.
  • Loss-of-function TBCK mutations are associated with reduced mechanistic target of rapamycin complex 1 (mTORC1) signaling.
  • mTORC1 signaling regulates autophagy, suggesting a potential link to neurodegeneration in TBCK-associated disorders.

Purpose of the Study:

  • To investigate autophagic-lysosomal dysfunction in TBCK-encephalopathy patients with a neurodegenerative course.
  • To characterize the neurological and systemic phenotype of TBCK-encephaloneuronopathy (TBCKE).
  • To explore the potential therapeutic effect of mTORC1 activation on autophagic dysfunction.

Main Methods:

  • Neurological phenotyping and neurophysiological studies in 8 children with TBCK p.R126X mutations.
  • Quantification of autophagosome content and autophagic markers in patient-derived fibroblasts.
  • Assay of free sialylated oligosaccharide profiles in patient urine and fibroblasts.

Main Results:

  • TBCK-encephaloneuronopathy (TBCKE) presents with congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, epilepsy, coarse facies, dyslipidemia, and osteoporosis.
  • TBCK-deficient fibroblasts show increased autophagosomes and autophagic flux.
  • Patients' urine and fibroblasts exhibit altered free oligosaccharide profiles, which are improved by leucine (mTORC1 activator).

Conclusions:

  • TBCK-encephaloneuronopathy (TBCKE) is a distinct syndrome characterized by progressive neurological dysfunction.
  • Inappropriate autophagy, independent of cellular stress, may contribute to TBCKE pathogenesis.
  • mTORC1 activation shows potential in ameliorating autophagic-lysosomal dysfunction, and oligosaccharide profiles may serve as biomarkers.

More Related Videos

Activating Autophagy by Aerobic Exercise in Mice08:44

Activating Autophagy by Aerobic Exercise in Mice

Published on: February 3, 2017

12.8K
Mass Histology to Quantify Neurodegeneration in Drosophila06:34

Mass Histology to Quantify Neurodegeneration in Drosophila

Published on: December 15, 2016

10.8K

Related Concept Videos

Mutations01:39

Mutations

Overview
94.7K
Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
44.7K
Autophagy01:27

Autophagy

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
5.9K
Viral Mutations00:36

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
40.0K
Mutation, Gene Flow, and Genetic Drift01:09

Mutation, Gene Flow, and Genetic Drift

In a population that is not at Hardy-Weinberg equilibrium, the frequency of alleles changes over time. Therefore, any deviations from the five conditions of Hardy-Weinberg equilibrium can alter the genetic variation of a given population. Conditions that change the genetic variability of a population include mutations, natural selection, non-random mating, gene flow, and genetic drift (small population size).
64.7K
Mutations in Microorganisms01:18

Mutations in Microorganisms

Mutations are heritable changes in an organism’s genome involving alterations in the base sequence of DNA or RNA. These changes can influence cellular processes and phenotypic traits, potentially transforming the unaltered wild type into a mutant form. Such changes, termed forward mutations, are pivotal in shaping the genetic diversity of organisms.RNA viruses exhibit the highest mutation rates due to the absence of robust proofreading mechanisms during genome replication. In contrast,...
793