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Am J Hum Genet. 2016 Oct 6;99(4):950-961. doi: 10.1016/j.ajhg.2016.08.005. Epub 2016 Sep 22.

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

Author information

1
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: nmiyake@yokohama-cu.ac.jp.
2
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
3
Department of Biological Science, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
4
Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; Agency for Medical Research and Development-Core Research for Evolutional Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
5
Department of Pathology, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan.
6
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
7
Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
8
Department of Neuropediatrics, Nagano Children's Hospital, Azumino 399-8205, Japan.
9
Division of Rehabilitation, Nagano Children's Hospital, Azumino 399-8205, Japan.
10
Department of Clinical Pathology, Nagano Children's Hospital, Azumino 399-8288, Japan.
11
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
12
Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur 50586, Malaysia.
13
Pediatric Neurology Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
14
Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan.
15
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan.
16
Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
17
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan; Department of Medical Genome Development, Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
18
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
19
Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
20
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
21
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.

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 β-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.

PMID:
27666374
PMCID:
PMC5065661
DOI:
10.1016/j.ajhg.2016.08.005
[Indexed for MEDLINE]
Free PMC Article

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