TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes
| Autor: | Raphael Schiffmann, Mona Bugaighis, Quasar S Padiath, Julian Curiel, Asako Takanohashi, Xiaoqin Fu, Judy S. Liu, Adeline Vanderver, Marjo S. van der Knaap, Guy Helman, Cas Simons, Guillermo Rodríguez Bey, Nicole I. Wolf, Marianna Bugiani, Bruce Nmezi, Tyler Mark Pierson |
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| Přispěvatelé: | Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pathology, Pediatric surgery |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Neurodegenerative medicine.disease_cause Bioinformatics Microtubules Medical and Health Sciences Basal Ganglia Myelin 0302 clinical medicine Tubulin Cerebellum 2.1 Biological and endogenous factors Aetiology Child Myelin Sheath Genetics (clinical) Neurons Genetics & Heredity Mutation Brain Articles General Medicine Middle Aged Biological Sciences Magnetic Resonance Imaging Phenotype Cell biology Oligodendroglia medicine.anatomical_structure Child Preschool Neurological Female Adult Cell type Adolescent Biology Cataract Young Adult 03 medical and health sciences Rare Diseases Atrophy Microtubule Genetics medicine Humans Preschool Molecular Biology Leukodystrophy Neurosciences Leukodystrophy Metachromatic Metachromatic medicine.disease Oligodendrocyte Brain Disorders Hereditary Central Nervous System Demyelinating Diseases 030104 developmental biology Hela Cells 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Human Molecular Genetics, 26(22), 4506-4518. Oxford University Press Curiel, J, Bey, G R, Takanohashi, A, Bugiani, M, Fu, X, Wolf, N I, Nmezi, B, Schiffmann, R, Bugaighis, M, Pierson, T, Helman, G, Simons, C, van der Knaap, M S, Liu, J, Padiath, Q & Vanderver, A 2017, ' TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes ', Human Molecular Genetics, vol. 26, no. 22, pp. 4506-4518 . https://doi.org/10.1093/hmg/ddx338 Human molecular genetics, vol 26, iss 22 Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition. |
| Databáze: | OpenAIRE |
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