@article{01a749dc382f4c779bd0122eaa93cb34,
title = "Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy",
abstract = "Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder. {\textcopyright} 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",
keywords = "developmental delay, intractable epilepsy, microcephaly, TBCD, tubulin, alpha tubulin, arginine, beta tubulin, chaperone, complementary DNA, threonine, tubulin cofactor D, unclassified drug, microtubule associated protein, TBCD protein, human, TBCD protein, zebrafish, zebrafish protein, adolescent, adult, allele, amino acid sequence, amino acid substitution, animal experiment, Article, autosomal recessive inheritance, B lymphocyte, binding site, brain cortex atrophy, child, clinical article, clinical feature, consanguinity, controlled study, corpus callosum, developmental disorder, embryo (anatomy), female, fibroblast, fibroblast culture, gene identification, gene overexpression, gene segregation, gene silencing, genetic association, genetic variability, genotype, heterozygote, human, immunofluorescence, intellectual impairment, intron, larva, male, microtubule assembly, molecular dynamics, myelination, nerve cell differentiation, nerve degeneration, nonhuman, nuclear magnetic resonance imaging, optic nerve atrophy, overlapping gene, pallor, phenotype, polymerase chain reaction, preschool child, priority journal, protein expression, protein function, protein structure, recessive inheritance, school child, sibling, Western blotting, whole exome sequencing, young adult, zebra fish, animal, case report, chemistry, diagnostic imaging, embryology, epilepsy, genetics, infant, metabolism, microtubule, nonmammalian embryo, pathology, seizure, Animals, Child, Preschool, Developmental Disabilities, Embryo, Nonmammalian, Epilepsy, Female, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Microcephaly, Microtubule-Associated Proteins, Microtubules, Seizures, Zebrafish, Zebrafish Proteins",
author = "B. Pode-Shakked and H. Barash and L. Ziv and K.W. Gripp and E. Flex and O. Barel and K.S. Carvalho and M. Scavina and G. Chillemi and M. Niceta and E. Eyal and N. Kol and B. Ben-Zeev and O. Bar-Yosef and D. Marek-Yagel and E. Bertini and A.L. Duker and Y. Anikster and M. Tartaglia and A. Raas-Rothschild",
note = "Cited By :3 Export Date: 10 April 2018 CODEN: CLGNA Correspondence Address: Tartaglia, M.; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges{\`u}Italy; email: marco.tartaglia@opbg.net Chemicals/CAS: alpha tubulin, 78769-62-7; arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; beta tubulin, 87090-36-6; threonine, 36676-50-3, 72-19-5; Microtubule-Associated Proteins; TBCD protein, human; TBCD protein, zebrafish; Zebrafish Proteins References: Kapitein, L.C., Hoogenraad, C.C., Building the neuronal microtubule cytoskeleton (2015) Neuron, 87 (3), pp. 492-506; Janke, C., The tubulin code: molecular components, readout mechanisms, and functions (2014) J Cell Biol, 206, pp. 461-472; Lewis, S.A., Tian, G., Cowan, N.J., The alpha- and beta-tubulin folding pathways (1997) Trends Cell Biol, 12, pp. 479-484; Tian, G., Lewis, S.A., Feierbach, B., Tubulin subunits exist in an activated conformational state generated and maintained by protein cofactors (1997) J Cell Biol, 138, pp. 821-832; L{\'o}pez-Fanarraga, M., Avila, J., Guasch, A., Review: postchaperone tubulin folding cofactors and their role in microtubule dynamics (2001) J Struct Biol, 135, pp. 219-229; Szymanski, D., Tubulin folding cofactors: half a dozen for a dimer (2002) Curr Biol, 12 (22), pp. R767-R769; Zhou, C., Chunningham, L., Marcus, A.I., Li, Y., Kahn, R.A., Arl2 and Arl3 regulate different microtubule-dependent processes (2006) Mol Biol Cell, 17, pp. 2476-2487; Parvari, R., Hershkovitz, E., Grossman, N., Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome (2002) Nat Genet, 32, pp. 448-452; Keays, D.A., Tian, G., Poirier, K., Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans (2007) Cell, 128, pp. 45-57; Jaglin, X.H., Poirier, K., Saillour, Y., Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria (2009) Nat Genet, 41, pp. 746-752; Tischfield, M.A., Cederquist, G.Y., Gupta, M.L., Jr., Engle, E.C., Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations (2011) Curr Opin Genet Dev, 21, pp. 286-294; Breus, M., Keays, D.A., Microtubules and neurodevelopmental disease: the movers and the makers (2014) Adv Exp Med Biol, 800, pp. 75-96; Simons, C., Wolf, N.I., McNeil, N., A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum (2013) Am J Hum Genet, 92 (5), pp. 767-773; Smith, B.N., Ticozzi, N., Fallini, C., Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS (2014) Neuron, 84 (2), pp. 324-331; Dubey, J., Ratnakaran, N., Koushika, S.P., Neurodegeneration and microtubule dynamics: death by a thousand cuts (2015) Front Cell Neurosci, 9, p. 343; Sferra, A., Baillat, G., Rizza, T., TBCE mutations cause early-onset progressive encephalopathy with distal spinal muscular atrophy (2016) Am J Hum Genet, 99 (4), pp. 974-983; Flex, E., Niceta, M., Cecchetti, S., Biallelic mutations in TBCD, encoding the tubulin folding cofactor D, perturb microtubule dynamics and cause early-onset encephalopathy (2016) Am J Hum Genet, 99 (4), pp. 962-973; Edvardson, S., Tian, G., Cullen, H., Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway (2016) Hum Mol Genet, , Epub ahead of print; Miyake, N., Fukai, R., Ohba, C., Biallelic TBCD mutations cause early-onset neurodegenerative encephalopathy (2016) Am J Hum Genet, 99 (4), pp. 950-961; Tian, G., Huang, Y., Rommelaere, H., Vandekerckhove, J., Ampe, C., Cowan, N.J., Pathway leading to correctly folded beta-tubulin (1996) Cell, 86 (2), pp. 287-296; Mart{\'i}n, L., Fanarraga, M.L., Aloria, K., Zabala, J.C., Tubulin folding cofactor D is a microtubule destabilizing protein (2000) FEBS Lett, 470 (1), pp. 93-95; Fanarraga, M.L., Bellido, J., Ja{\'e}n, C., Villegas, J.C., Zabala, J.C., TBCD links centriologenesis, spindle microtubule dynamics, and midbody abscission in human cells (2010) PLoS One, 5 (1); Cunningham, L.A., Kahn, R.A., Cofactor D functions as a centrosomal protein and is required for the recruitment of the gamma-tubulin ring complex at centrosomes and organization of the mitotic spindle (2008) J Biol Chem, 283 (11), pp. 7155-7165; Tian, G., Thomas, S., Cowan, N.J., Effect of TBCD and its regulatory interactor Arl2 on tubulin and microtubule integrity (2010) Cytoskeleton (Hoboken), 67 (11), pp. 706-714; Okumura, M., Sakuma, C., Miura, M., Chihara, T., Linking cell surface receptors to microtubules: tubulin folding cofactor D mediates Dscam functions during neuronal morphogenesis (2015) J Neurosci, 35 (5), pp. 1979-1990; Bahi-Buisson, N., Poirier, K., Fourniol, F., The wide spectrum of tubulinopathies: what are the key features for the diagnosis? (2014) Brain, 137, pp. 1676-1700; Sakuma, C., Okumura, M., Umehara, T., Miura, M., Chihara, T., A STRIPAK component strip regulates neuronal morphogenesis by affecting microtubule stability (2015) Sci Rep, 5, p. 17769; Poulton, C.J., Schot, R., Seufert, K., Severe presentation of WDR62 mutation: is there a role for modifying genetic factors? (2014) Am J Med Genet A, 164 (9), pp. 2161-2171; Xu, X., Hu, Y., Xiong, Y., Association of microtubule dynamics with chronic epilepsy (2016) Mol Neurobiol, 53 (7), pp. 5013-5024; Waldman, Y.Y., Biddanda, A., Dubrovsky, M., The genetic history of Cochin Jews from India (2016) Hum Genet, 135 (10), pp. 27-43; Brouhard, G.J., Dynamic instability 30 years later: complexities in microtubule growth and catastrophe (2015) Mol Biol Cell, 26 (7), pp. 1207-1210",
year = "2017",
doi = "10.1111/cge.12914",
language = "English",
volume = "91",
pages = "725--738",
journal = "Clinical Genetics",
issn = "0009-9163",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "5",
}