Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

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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.

American Society of Human Genetics

Aviva Fattal-Valevski

10-06-2016

American Journal of Human Genetics

Affiliations

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