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Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies
Satoko Miyatake1, Hitoshi Osaka1, Masaaki Shiina1
1From 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.
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.
Insights
Mutations in the TUBB4A gene cause hypomyelinating leukoencephalopathies (H-ABC), expanding the known clinical spectrum. Extrapyramidal symptoms can indicate TUBB4A involvement in these rare neurological disorders.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Hypomyelinating leukoencephalopathies are a group of rare genetic disorders characterized by impaired myelin formation.
- Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a severe form, but the genetic basis for some cases remains unknown.
Purpose of the Study:
- To investigate the genetic causes of unsolved hypomyelinating leukoencephalopathies.
- To define the phenotypic spectrum associated with TUBB4A mutations.
Main Methods:
- Whole-exome sequencing was performed on 14 patients with hypomyelinating leukoencephalopathies.
- The functional impact of identified TUBB4A mutations was assessed using 3D models of αβ-tubulin heterodimers.
Main Results:
- Six heterozygous missense TUBB4A mutations, five novel, were found in 8 patients, including those with H-ABC and unclassified hypomyelinating leukoencephalopathy.
- Mutations affected microtubule structure and protein interactions, with distinct mechanisms observed for different mutations.
- Patients with the p.Glu410Lys mutation showed basal ganglia functional impairment without significant atrophy, alongside extrapyramidal features.
Conclusions:
- TUBB4A mutations are confirmed to cause typical H-ABC.
- The findings broaden the spectrum of TUBB4A-related hypomyelinating leukoencephalopathies, including cases with functionally impaired basal ganglia.
- Extrapyramidal signs are highlighted as a potential diagnostic clue for TUBB4A mutations in hypomyelinating leukoencephalopathies.
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