TUBB4A de novo mutations cause isolated hypomyelination

Pizzino, Amy, Pierson, Tyler Mark, Guo, Yiran, Helman, Guy, Fortini, Sebastian, Guerrero, Kether, Saitta, Sulagna, Murphy, Jennifer Louise Patrick, Padiath, Quasar, Xie, Yi, Hakonarson, Hakon, Xu, Xun, Funari, Tara, Fox, Michelle, Taft, Ryan J., van der Knaap, Marjo S., Bernard, Genevieve, Schiffmann, Raphael, Simons, Cas and Vanderver, Adeline (2014) TUBB4A de novo mutations cause isolated hypomyelination. Neurology, 83 10: 898-902. doi:10.1212/WNL.0000000000000754

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Author Pizzino, Amy
Pierson, Tyler Mark
Guo, Yiran
Helman, Guy
Fortini, Sebastian
Guerrero, Kether
Saitta, Sulagna
Murphy, Jennifer Louise Patrick
Padiath, Quasar
Xie, Yi
Hakonarson, Hakon
Xu, Xun
Funari, Tara
Fox, Michelle
Taft, Ryan J.
van der Knaap, Marjo S.
Bernard, Genevieve
Schiffmann, Raphael
Simons, Cas
Vanderver, Adeline
Title TUBB4A de novo mutations cause isolated hypomyelination
Journal name Neurology   Check publisher's open access policy
ISSN 0028-3878
Publication date 2014-09-01
Year available 2014
Sub-type Article (original research)
DOI 10.1212/WNL.0000000000000754
Open Access Status File (Publisher version)
Volume 83
Issue 10
Start page 898
End page 902
Total pages 5
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Subject 2728 Clinical Neurology
Abstract 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.
Formatted abstract
Objective: We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations.

Methods: Patients in 2 large institutional review board–approved leukodystrophy bioregistries at Children’s National Medical Center and Montreal Children’s Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed.

Results: Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations.

Conclusion: Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered in cases of isolated hypomyelination or hypomyelination with nonspecific cerebellar atrophy. N
Keyword Pelizaeus-Merzbacher Disease
Basal Ganglia
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
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Created: Sun, 12 Oct 2014, 10:46:01 EST by System User on behalf of Institute for Molecular Bioscience