Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy

B. Pode-Shakked, H. Barash, L. Ziv, K.W. Gripp, E. Flex, O. Barel, K.S. Carvalho, M. Scavina, G. Chillemi, M. Niceta, E. Eyal, N. Kol, B. Ben-Zeev, O. Bar-Yosef, D. Marek-Yagel, E. Bertini, A.L. Duker, Y. Anikster, M. Tartaglia, A. Raas-Rothschild

Research output: Contribution to journalArticlepeer-review


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. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Original languageEnglish
Pages (from-to)725-738
Number of pages14
JournalClinical Genetics
Issue number5
Publication statusPublished - 2017


  • 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


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