Satoko Miyatake1, Hitoshi Osaka1, Masaaki Shiina1, Masayuki Sasaki1, Jun-Ichi Takanashi1, Kazuhiro Haginoya1, Takahito Wada1, Masafumi Morimoto1, Naoki Ando1, Yoji Ikuta1, Mitsuko Nakashima1, Yoshinori Tsurusaki1, Noriko Miyake1, Kazuhiro Ogata1, Naomichi Matsumoto2, Hirotomo Saitsu2. 1. From the Departments of Human Genetics (S.M., M.N., Y.T., N. Miyake, N. Matsumoto, H.S.) and Biochemistry (M. Shiina, K.O.), Yokohama City University Graduate School of Medicine; Division of Neurology (H.O.), Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (H.O.), Jichi Medical School, Tochigi; Department of Child Neurology (M. Sasaki), National Center of Neurology and Psychiatry, Tokyo; Department of Pediatrics (J.-i.T.), Kameda Medical Center, Chiba; Department of Pediatric Neurology (K.H.), Takuto Rehabilitation Center for Children, Sendai; Genetic Counselling and Clinical Research Unit (T.W.), Kyoto University School of Public Health; Department of Pediatrics (M.M.), Graduate School of Medical Science, Kyoto Prefectural University of Medicine; Department of Neonatology and Pediatrics (N.A.), Nagoya City University Graduate School of Medical Sciences; and Department of Neurology (Y.I.), Tokyo Metropolitan Children's Medical Center, Japan. 2. From the Departments of Human Genetics (S.M., M.N., Y.T., N. Miyake, N. Matsumoto, H.S.) and Biochemistry (M. Shiina, K.O.), Yokohama City University Graduate School of Medicine; Division of Neurology (H.O.), Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (H.O.), Jichi Medical School, Tochigi; Department of Child Neurology (M. Sasaki), National Center of Neurology and Psychiatry, Tokyo; Department of Pediatrics (J.-i.T.), Kameda Medical Center, Chiba; Department of Pediatric Neurology (K.H.), Takuto Rehabilitation Center for Children, Sendai; Genetic Counselling and Clinical Research Unit (T.W.), Kyoto University School of Public Health; Department of Pediatrics (M.M.), Graduate School of Medical Science, Kyoto Prefectural University of Medicine; Department of Neonatology and Pediatrics (N.A.), Nagoya City University Graduate School of Medical Sciences; and Department of Neurology (Y.I.), Tokyo Metropolitan Children's Medical Center, Japan. naomat@yokohama-cu.ac.jp hsaitsu@yokohama-cu.ac.jp.
Abstract
OBJECTIVE: We performed whole-exome sequencing analysis of patients with genetically unsolved hypomyelinating leukoencephalopathies, identifying 8 patients with TUBB4A mutations and allowing the phenotypic spectrum of TUBB4A mutations to be investigated. METHODS: Fourteen patients with hypomyelinating leukoencephalopathies, 7 clinically diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and 7 with unclassified hypomyelinating leukoencephalopathy, were analyzed by whole-exome sequencing. The effect of the mutations on microtubule assembly was examined by mapping altered amino acids onto 3-dimensional models of the αβ-tubulin heterodimer. RESULTS: Six heterozygous missense mutations in TUBB4A, 5 of which are novel, were identified in 8 patients (6/7 patients with H-ABC [the remaining patient is an atypical case] and 2/7 patients with unclassified hypomyelinating leukoencephalopathy). In 4 cases with parental samples available, the mutations occurred de novo. Analysis of 3-dimensional models revealed that the p.Glu410Lys mutation, identified in patients with unclassified hypomyelinating leukoencephalopathy, directly impairs motor protein and/or microtubule-associated protein interactions with microtubules, whereas the other mutations affect longitudinal interactions for maintaining αβ-tubulin structure, suggesting different mechanisms in tubulin function impairment. In patients with the p.Glu410Lys mutation, basal ganglia atrophy was unobserved or minimal although extrapyramidal features were detected, suggesting its functional impairment. CONCLUSIONS: TUBB4A mutations cause typical H-ABC. Furthermore, TUBB4A mutations associate cases of unclassified hypomyelinating leukoencephalopathies with morphologically retained but functionally impaired basal ganglia, suggesting that TUBB4A-related hypomyelinating leukoencephalopathies encompass a broader clinical spectrum than previously expected. Extrapyramidal findings may be a key for consideration of TUBB4A mutations in hypomyelinating leukoencephalopathies.
OBJECTIVE: We performed whole-exome sequencing analysis of patients with genetically unsolved hypomyelinating leukoencephalopathies, identifying 8 patients with TUBB4A mutations and allowing the phenotypic spectrum of TUBB4A mutations to be investigated. METHODS: Fourteen patients with hypomyelinating leukoencephalopathies, 7 clinically diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and 7 with unclassified hypomyelinating leukoencephalopathy, were analyzed by whole-exome sequencing. The effect of the mutations on microtubule assembly was examined by mapping altered amino acids onto 3-dimensional models of the αβ-tubulin heterodimer. RESULTS: Six heterozygous missense mutations in TUBB4A, 5 of which are novel, were identified in 8 patients (6/7 patients with H-ABC [the remaining patient is an atypical case] and 2/7 patients with unclassified hypomyelinating leukoencephalopathy). In 4 cases with parental samples available, the mutations occurred de novo. Analysis of 3-dimensional models revealed that the p.Glu410Lys mutation, identified in patients with unclassified hypomyelinating leukoencephalopathy, directly impairs motor protein and/or microtubule-associated protein interactions with microtubules, whereas the other mutations affect longitudinal interactions for maintaining αβ-tubulin structure, suggesting different mechanisms in tubulin function impairment. In patients with the p.Glu410Lys mutation, basal ganglia atrophy was unobserved or minimal although extrapyramidal features were detected, suggesting its functional impairment. CONCLUSIONS:TUBB4A mutations cause typical H-ABC. Furthermore, TUBB4A mutations associate cases of unclassified hypomyelinating leukoencephalopathies with morphologically retained but functionally impaired basal ganglia, suggesting that TUBB4A-related hypomyelinating leukoencephalopathies encompass a broader clinical spectrum than previously expected. Extrapyramidal findings may be a key for consideration of TUBB4A mutations in hypomyelinating leukoencephalopathies.
Authors: Claudio M de Gusmão; Tania Fuchs; Andrew Moses; Trisha Multhaupt-Buell; Phillip C Song; Laurie J Ozelius; Ramon A Franco; Nutan Sharma Journal: Otolaryngol Head Neck Surg Date: 2016-05-17 Impact factor: 3.497