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Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

ABSTRACT: We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and ?-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

SUBMITTER: Miyake N

PROVIDER: S-EPMC5065661 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

Miyake Noriko N Fukai Ryoko R Ohba Chihiro C Chihara Takahiro T Miura Masayuki M Shimizu Hiroshi H Kakita Akiyoshi A Imagawa Eri E Shiina Masaaki M Ogata Kazuhiro K Okuno-Yuguchi Jiu J Fueki Noboru N Ogiso Yoshifumi Y Suzumura Hiroshi H Watabe Yoshiyuki Y Imataka George G Leong Huey Yin HY Fattal-Valevski Aviva A Kramer Uri U Miyatake Satoko S Kato Mitsuhiro M Okamoto Nobuhiko N Sato Yoshinori Y Mitsuhashi Satomi S Nishino Ichizo I Kaneko Naofumi N Nishiyama Akira A Tamura Tomohiko T Mizuguchi Takeshi T Nakashima Mitsuko M Tanaka Fumiaki F Saitsu Hirotomo H Matsumoto Naomichi N

American journal of human genetics 20160922 4

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a ...[more]

PMID: 27666374

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Project description: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.

Dataset Information

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

Publications

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

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