HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy.

Abstract
Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia. Molecular dynamics simulations predicted long-range and/or local structural perturbations associated with the disease-causing mutations. Biochemical analyses documented variably reduced levels of TBCD, indicating relative instability of mutant proteins, and defective β-tubulin binding in a subset of the tested mutants. Reduced or defective TBCD function resulted in decreased soluble α/β-tubulin levels and accelerated microtubule polymerization in fibroblasts from affected subjects, demonstrating an overall shift toward a more rapidly growing and stable microtubule population. These cells displayed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, which however did not alter appreciably the rate of cell proliferation. Our findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain.
AuthorsElisabetta Flex, Marcello Niceta, Serena Cecchetti, Isabelle Thiffault, Margaret G Au, Alessandro Capuano, Emanuela Piermarini, Anna A Ivanova, Joshua W Francis, Giovanni Chillemi, Balasubramanian Chandramouli, Giovanna Carpentieri, Charlotte A Haaxma, Andrea Ciolfi, Simone Pizzi, Ganka V Douglas, Kara Levine, Antonella Sferra, Maria Lisa Dentici, Rolph R Pfundt, Jean-Baptiste Le Pichon, Emily Farrow, Frank Baas, Fiorella Piemonte, Bruno Dallapiccola, John M Graham Jr, Carol J Saunders, Enrico Bertini, Richard A Kahn, David A Koolen, Marco Tartaglia
JournalAmerican journal of human genetics (Am J Hum Genet) Vol. 99 Issue 4 Pg. 962-973 (Oct 06 2016) ISSN: 1537-6605 [Electronic] United States
PMID27666370 (Publication Type: Journal Article)
CopyrightCopyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Microtubule-Associated Proteins
  • Molecular Chaperones
  • TBCD protein, human
  • Tubulin
Topics
  • Adolescent
  • Age of Onset
  • Alleles
  • Brain (metabolism, pathology)
  • Brain Diseases (genetics, pathology)
  • Cell Proliferation
  • Child, Preschool
  • Female
  • Fibroblasts
  • Humans
  • Infant
  • Male
  • Microtubule-Associated Proteins (genetics, metabolism)
  • Microtubules (metabolism, pathology)
  • Molecular Chaperones (genetics, metabolism)
  • Mutation
  • Protein Binding
  • Protein Folding
  • Spindle Apparatus (metabolism, pathology)
  • Tubulin (chemistry, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: