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

Elisabetta 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. PfundtJean Baptiste Le Pichon, Emily Farrow, Frank Baas, Fiorella Piemonte, Bruno Dallapiccola, John M. Graham, Carol J. Saunders, Enrico Bertini, Richard A. Kahn, David A. Koolen, Marco Tartaglia

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)962-973
Number of pages12
JournalAmerican Journal of Human Genetics
Volume99
Issue number4
DOIs
Publication statusPublished - Oct 6 2016

Fingerprint

Brain Diseases
Tubulin
Microtubules
Mutation
Polymerization
Optic Atrophy
Microcephaly
Spindle Apparatus
Quadriplegia
Microtubule-Associated Proteins
Corpus Callosum
Population Dynamics
Mutant Proteins
Molecular Dynamics Simulation
Intellectual Disability
Neurodegenerative Diseases
Cell Division
Atrophy
Cell Movement
Signal Transduction

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. / Flex, Elisabetta; Niceta, Marcello; Cecchetti, Serena; Thiffault, Isabelle; Au, Margaret G.; Capuano, Alessandro; Piermarini, Emanuela; Ivanova, Anna A.; Francis, Joshua W.; Chillemi, Giovanni; Chandramouli, Balasubramanian; Carpentieri, Giovanna; Haaxma, Charlotte A.; Ciolfi, Andrea; Pizzi, Simone; Douglas, Ganka V.; Levine, Kara; Sferra, Antonella; Dentici, Maria Lisa; Pfundt, Rolph R.; Le Pichon, Jean Baptiste; Farrow, Emily; Baas, Frank; Piemonte, Fiorella; Dallapiccola, Bruno; Graham, John M.; Saunders, Carol J.; Bertini, Enrico; Kahn, Richard A.; Koolen, David A.; Tartaglia, Marco.

In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 962-973.

Research output: Contribution to journalArticle

Flex, E, Niceta, M, Cecchetti, S, Thiffault, I, Au, MG, Capuano, A, Piermarini, E, Ivanova, AA, Francis, JW, Chillemi, G, Chandramouli, B, Carpentieri, G, Haaxma, CA, Ciolfi, A, Pizzi, S, Douglas, GV, Levine, K, Sferra, A, Dentici, ML, Pfundt, RR, Le Pichon, JB, Farrow, E, Baas, F, Piemonte, F, Dallapiccola, B, Graham, JM, Saunders, CJ, Bertini, E, Kahn, RA, Koolen, DA & Tartaglia, M 2016, 'Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy', American Journal of Human Genetics, vol. 99, no. 4, pp. 962-973. https://doi.org/10.1016/j.ajhg.2016.08.003
Flex, Elisabetta ; Niceta, Marcello ; Cecchetti, Serena ; Thiffault, Isabelle ; Au, Margaret G. ; Capuano, Alessandro ; Piermarini, Emanuela ; Ivanova, Anna A. ; Francis, Joshua W. ; Chillemi, Giovanni ; Chandramouli, Balasubramanian ; Carpentieri, Giovanna ; Haaxma, Charlotte A. ; Ciolfi, Andrea ; Pizzi, Simone ; Douglas, Ganka V. ; Levine, Kara ; Sferra, Antonella ; Dentici, Maria Lisa ; Pfundt, Rolph R. ; Le Pichon, Jean Baptiste ; Farrow, Emily ; Baas, Frank ; Piemonte, Fiorella ; Dallapiccola, Bruno ; Graham, John M. ; Saunders, Carol J. ; Bertini, Enrico ; Kahn, Richard A. ; Koolen, David A. ; Tartaglia, Marco. / Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 4. pp. 962-973.
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AU - Flex, Elisabetta

AU - Niceta, Marcello

AU - Cecchetti, Serena

AU - Thiffault, Isabelle

AU - Au, Margaret G.

AU - Capuano, Alessandro

AU - Piermarini, Emanuela

AU - Ivanova, Anna A.

AU - Francis, Joshua W.

AU - Chillemi, Giovanni

AU - Chandramouli, Balasubramanian

AU - Carpentieri, Giovanna

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AU - Pizzi, Simone

AU - Douglas, Ganka V.

AU - Levine, Kara

AU - Sferra, Antonella

AU - Dentici, Maria Lisa

AU - Pfundt, Rolph R.

AU - Le Pichon, Jean Baptiste

AU - Farrow, Emily

AU - Baas, Frank

AU - Piemonte, Fiorella

AU - Dallapiccola, Bruno

AU - Graham, John M.

AU - Saunders, Carol J.

AU - Bertini, Enrico

AU - Kahn, Richard A.

AU - Koolen, David A.

AU - Tartaglia, Marco

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