Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.
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.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: nmiyake@yokohama-cu.ac.jp.
Noriko
N
Miyake
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.
Ryoko
R
Fukai
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.
Chihiro
C
Ohba
Department of Biological Science, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
Takahiro
T
Chihara
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.
Masayuki
M
Miura
Department of Pathology, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan.
Hiroshi
H
Shimizu
Department of Pathology, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan.
Akiyoshi
A
Kakita
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Eri
E
Imagawa
Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Masaaki
M
Shiina
Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Kazuhiro
K
Ogata
Department of Neuropediatrics, Nagano Children's Hospital, Azumino 399-8205, Japan.
Jiu
J
Okuno-Yuguchi
Division of Rehabilitation, Nagano Children's Hospital, Azumino 399-8205, Japan.
Noboru
N
Fueki
Department of Clinical Pathology, Nagano Children's Hospital, Azumino 399-8288, Japan.
Yoshifumi
Y
Ogiso
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
Hiroshi
H
Suzumura
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
Yoshiyuki
Y
Watabe
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
George
G
Imataka
Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur 50586, Malaysia.
Huey Yin
HY
Leong
Pediatric Neurology Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Aviva
A
Fattal-Valevski
Pediatric Neurology Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Uri
U
Kramer
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Satoko
S
Miyatake
Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan.
Mitsuhiro
M
Kato
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan.
Nobuhiko
N
Okamoto
Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Yoshinori
Y
Sato
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.
Satomi
S
Mitsuhashi
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.
Ichizo
I
Nishino
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Naofumi
N
Kaneko
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Akira
A
Nishiyama
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Tomohiko
T
Tamura
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Takeshi
T
Mizuguchi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Mitsuko
M
Nakashima
Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Fumiaki
F
Tanaka
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
Hirotomo
H
Saitsu
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.
Naomichi
N
Matsumoto
D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004331:Drosophila melanogaster / Q000235:genetics; D059472:Exome; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D014404:Tubulin / Q000378:metabolism; D055815:Young Adult
D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D022821:RNA Splice Sites; C418662:TBCD protein, human; C469270:TBCE protein, human; D014404:Tubulin; C410130:ARL2 protein, human; D019204:GTP-Binding Proteins
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