1. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy
- Author
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Akira Nishiyama, Aviva Fattal-Valevski, Satoko Miyatake, Hiroshi Suzumura, Eri Imagawa, Uri Kramer, Fumiaki Tanaka, Hiroshi Shimizu, Ryoko Fukai, Nobuhiko Okamoto, Chihiro Ohba, Takahiro Chihara, Kazuhiro Ogata, Akiyoshi Kakita, Noriko Miyake, Jiu Okuno-Yuguchi, Yoshinori Sato, Yoshifumi Ogiso, Naofumi Kaneko, Naomichi Matsumoto, Mitsuhiro Kato, Tomohiko Tamura, Noboru Fueki, Huey Yin Leong, Masaaki Shiina, George Imataka, Hirotomo Saitsu, Masayuki Miura, Mitsuko Nakashima, Satomi Mitsuhashi, Yoshiyuki Watabe, Takeshi Mizuguchi, and Ichizo Nishino
- Subjects
Male ,0301 basic medicine ,Cerebellum ,Adolescent ,Encephalopathy ,Postnatal microcephaly ,Biology ,Microtubules ,Frameshift mutation ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,GTP-Binding Proteins ,Tubulin ,Report ,Genetics ,medicine ,Animals ,Humans ,Missense mutation ,Exome ,Amino Acid Sequence ,Age of Onset ,Child ,Frameshift Mutation ,Alleles ,Genetics (clinical) ,Loss function ,Brain Diseases ,Splice site mutation ,Infant, Newborn ,Infant ,Neurodegenerative Diseases ,medicine.disease ,Pedigree ,Drosophila melanogaster ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Mutation ,Female ,RNA Splice Sites ,Microtubule-Associated Proteins ,030217 neurology & neurosurgery ,Molecular Chaperones - 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.
- Published
- 2016