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Article: MAPping tubulin mutations.

Cushion, Thomas D / Leca, Ines / Keays, David A

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1136699

Abstract: Microtubules are filamentous structures that play a critical role in a diverse array of cellular functions including, mitosis, nuclear translocation, trafficking of organelles and cell shape. They are composed of α/β-tubulin heterodimers which are ... ...

Abstract	Microtubules are filamentous structures that play a critical role in a diverse array of cellular functions including, mitosis, nuclear translocation, trafficking of organelles and cell shape. They are composed of α/β-tubulin heterodimers which are encoded by a large multigene family that has been implicated in an umbrella of disease states collectively known as the tubulinopathies.
Language	English
Publishing date	2023-02-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1136699
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Article ; Online: The genetics of lissencephaly.

Fry, Andrew E / Cushion, Thomas D / Pilz, Daniela T

American journal of medical genetics. Part C, Seminars in medical genetics

2014 Volume 166C, Issue 2, Page(s) 198–210

Abstract: Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been characterized in recent years. ... ...

Abstract	Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been characterized in recent years. Identification of the genetic basis of these disorders has brought fascinating insights into the mechanisms of brain development, as well as benefits to patients through improved molecular diagnosis and genetic counseling. This review explores the clinical presentation, radiological features, histological findings and molecular basis of lissencephaly with the aim of facilitating the selection and interpretation of gene tests in patients with 'smooth brain' phenotypes.
MeSH term(s)	Animals ; Genetic Heterogeneity ; Humans ; Lissencephaly/genetics ; Lissencephaly/pathology ; Magnetic Resonance Imaging ; Mutation ; Neuroimaging ; Phenotype
Language	English
Publishing date	2014-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2108622-9
ISSN	1552-4876 ; 0148-7299 ; 1552-4868
ISSN (online)	1552-4876
ISSN	0148-7299 ; 1552-4868
DOI	10.1002/ajmg.c.31402
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Article ; Online: Tubulin genes and malformations of cortical development.

Romaniello, Romina / Arrigoni, Filippo / Fry, Andrew E / Bassi, Maria T / Rees, Mark I / Borgatti, Renato / Pilz, Daniela T / Cushion, Thomas D

European journal of medical genetics

2018 Volume 61, Issue 12, Page(s) 744–754

Abstract: A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal ... ...

Abstract	A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation. The major tubulin subclasses (alpha- and beta-tubulin) share high sequence and structural homology. These globular proteins form heterodimers and subsequently co-assemble into microtubules. Microtubules are dynamic, cytoskeletal polymers which play key roles in cellular processes crucial for cortical development, including neuronal proliferation, migration and cortical laminar organisation. Mutations in seven genes encoding alpha-tubulin (TUBA1A), beta-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB) and gamma-tubulin (TUBG1) isoforms have been associated with a wide and overlapping range of brain malformations or "Tubulinopathies". The majority of cortical phenotypes include lissencephaly, polymicrogyria, microlissencephaly and simplified gyration. Well-known hallmarks of the tubulinopathies include dysmorphism of the basal ganglia (fusion of the caudate nucleus and putamen with absence of the anterior limb of the internal capsule), midline commissural structures hypoplasia and/or agenesis (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, cerebellar hypoplasia or dysplasia and dysmorphism of the hind-brain structures. The cortical and extra-cortical brain phenotypes observed are largely dependent on the specific tubulin gene affected. In the present review, all the published data on tubulin family gene mutations and the associated cortical phenotypes are summarized. In addition, the most typical neuroimaging patterns of malformations of cortical development associated with tubulin gene mutations detected on the basis of our own experience are described.
MeSH term(s)	Basal Ganglia/pathology ; Brain/diagnostic imaging ; Brain/growth & development ; Brain/pathology ; Cell Differentiation/genetics ; Corpus Callosum/pathology ; Humans ; Malformations of Cortical Development/diagnostic imaging ; Malformations of Cortical Development/genetics ; Malformations of Cortical Development/pathology ; Mutation ; Neuroimaging ; Tubulin/genetics
Chemical Substances	TUBA1A protein, human ; Tubulin
Language	English
Publishing date	2018-07-17
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2184135-4
ISSN	1878-0849 ; 1769-7212
ISSN (online)	1878-0849
ISSN	1769-7212
DOI	10.1016/j.ejmg.2018.07.012
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Article ; Online: The biophysical, molecular, and anatomical landscape of pigeon CRY4: A candidate light-based quantal magnetosensor.

Science advances

2020 Volume 6, Issue 33, Page(s) eabb9110

Abstract: The biophysical and molecular mechanisms that enable animals to detect magnetic fields are unknown. It has been proposed that birds have a light-dependent magnetic compass that relies on the formation of radical pairs within cryptochrome molecules. Using ...

Abstract	The biophysical and molecular mechanisms that enable animals to detect magnetic fields are unknown. It has been proposed that birds have a light-dependent magnetic compass that relies on the formation of radical pairs within cryptochrome molecules. Using spectroscopic methods, we show that pigeon cryptochrome clCRY4 is photoreduced efficiently and forms long-lived spin-correlated radical pairs via a tetrad of tryptophan residues. We report that clCRY4 is broadly and stably expressed within the retina but enriched at synapses in the outer plexiform layer in a repetitive manner. A proteomic survey for retinal-specific clCRY4 interactors identified molecules that are involved in receptor signaling, including glutamate receptor-interacting protein 2, which colocalizes with clCRY4. Our data support a model whereby clCRY4 acts as an ultraviolet-blue photoreceptor and/or a light-dependent magnetosensor by modulating glutamatergic synapses between horizontal cells and cones.
Language	English
Publishing date	2020-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abb9110
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Article: Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.

Gardner, Jennifer F / Cushion, Thomas D / Niotakis, Georgios / Olson, Heather E / Grant, P Ellen / Scott, Richard H / Stoodley, Neil / Cohen, Julie S / Naidu, Sakkubai / Attie-Bitach, Tania / Bonnières, Maryse / Boutaud, Lucile / Encha-Razavi, Férechté / Palmer-Smith, Sheila M / Mugalaasi, Hood / Mullins, Jonathan G L / Pilz, Daniela T / Fry, Andrew E

Brain sciences

2018 Volume 8, Issue 8

Abstract: ... ...

Abstract	The
Language	English
Publishing date	2018-08-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci8080145
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Article ; Online: De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy.

Cushion, Thomas D / Paciorkowski, Alex R / Pilz, Daniela T / Mullins, Jonathan G L / Seltzer, Laurie E / Marion, Robert W / Tuttle, Emily / Ghoneim, Dalia / Christian, Susan L / Chung, Seo-Kyung / Rees, Mark I / Dobyns, William B

American journal of human genetics

2014 Volume 94, Issue 4, Page(s) 634–641

Abstract: Tubulins, and microtubule polymers into which they incorporate, play critical mechanical roles in neuronal function during cell proliferation, neuronal migration, and postmigrational development: the three major overlapping events of mammalian cerebral ... ...

Abstract	Tubulins, and microtubule polymers into which they incorporate, play critical mechanical roles in neuronal function during cell proliferation, neuronal migration, and postmigrational development: the three major overlapping events of mammalian cerebral cortex development. A number of neuronally expressed tubulin genes are associated with a spectrum of disorders affecting cerebral cortex formation. Such "tubulinopathies" include lissencephaly/pachygyria, polymicrogyria-like malformations, and simplified gyral patterns, in addition to characteristic extracortical features, such as corpus callosal, basal ganglia, and cerebellar abnormalities. Epilepsy is a common finding in these related disorders. Here we describe two unrelated individuals with infantile-onset epilepsy and abnormalities of brain morphology, harboring de novo variants that affect adjacent amino acids in a beta-tubulin gene TUBB2A. Located in a highly conserved loop, we demonstrate impaired tubulin and microtubule function resulting from each variant in vitro and by using in silico predictive modeling. We propose that the affected functional loop directly associates with the alpha-tubulin-bound guanosine triphosphate (GTP) molecule, impairing the intradimer interface and correct formation of the alpha/beta-tubulin heterodimer. This study associates mutations in TUBB2A with the spectrum of "tubulinopathy" phenotypes. As a consequence, genetic variations affecting all beta-tubulin genes expressed at high levels in the brain (TUBB2B, TUBB3, TUBB, TUBB4A, and TUBB2A) have been linked with malformations of cortical development.
MeSH term(s)	Amino Acid Sequence ; Dentate Gyrus/pathology ; Epilepsy/genetics ; Epilepsy/pathology ; HEK293 Cells ; Humans ; Infant ; Magnetic Resonance Imaging ; Models, Molecular ; Molecular Sequence Data ; Mutation, Missense ; Sequence Homology, Amino Acid ; Tubulin/chemistry ; Tubulin/genetics
Chemical Substances	Tubulin
Language	English
Publishing date	2014-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2014.03.009
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Article ; Online: Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay.

Thomas, Rhys H / Chung, Seo-Kyung / Wood, Sian E / Cushion, Thomas D / Drew, Cheney J G / Hammond, Carrie L / Vanbellinghen, Jean-Francois / Mullins, Jonathan G L / Rees, Mark I

Brain : a journal of neurology

2013 Volume 136, Issue Pt 10, Page(s) 3085–3095

Abstract: Congenital hyperekplexia is a rare, potentially treatable neuromotor disorder. Three major genes of effect are known, and all three affect glycinergic neurotransmission. Two genes encode for subunits of the postsynaptic inhibitory glycine receptor, GLRA1 ...

Abstract	Congenital hyperekplexia is a rare, potentially treatable neuromotor disorder. Three major genes of effect are known, and all three affect glycinergic neurotransmission. Two genes encode for subunits of the postsynaptic inhibitory glycine receptor, GLRA1 encoding the α1 subunit and GLRB encoding the β subunit. The third, SLC6A5, encodes the cognate presynaptic glycine transporter 2. Ninety-seven individuals had a clinical diagnosis of hyperekplexia confirmed by genetic testing: 61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB. Detailed retrospective clinical analysis ascertained that all gene-positive cases present in the neonatal period (occasionally prenatally) and that clonazepam is the treatment of choice (95% found it to be efficacious). We confirm that hyperekplexia is predominantly a recessive condition but dominant cases are seen (16%). We found no genetic evidence for 'major' or 'minor' forms of hyperekplexia on a population basis. Thirty-five gene-negative cases were studied for comparison, their cardinal feature was presentation after the first month of life (P < 0.001). In addition to the characteristic 'stiffness, startles and stumbles' of hyperekplexia, apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported. Patients with SLC6A5 mutations were significantly more likely to have had recurrent infantile apnoeas (RR1.9; P < 0.005) than those with GLRA1 mutations. Patients with GLRB and SLC6A5 mutations were more likely to have developmental delay (RR1.5 P < 0.01; RR1.9 P < 0.03) than those with GLRA1 mutations; 92% of GLRB cases reported a mild to severe delay in speech acquisition. Molecular modelling of pathogenic mutations demonstrates specific patterns of protein disruption that can be used to predict phenotype severity. The developmental delay in hyperekplexia, and speech acquisition in particular, may represent failure of developmental neural networks or subtle neurogenic migration defects in the absence of presynaptic glycine release. We recommend early genetic testing for symptomatic neonates and possibly preconception counselling for those at risk for GLRB and SLC6A5 mutations, because of the more challenging phenotype.
MeSH term(s)	Adolescent ; Adult ; Epilepsy/genetics ; Female ; Genetic Association Studies ; Genetic Diseases, X-Linked/genetics ; Genetic Predisposition to Disease ; Humans ; Language Development Disorders/genetics ; Learning/physiology ; Male ; Mutation/genetics ; Phenotype ; Receptors, Glycine/genetics ; Reflex, Abnormal/genetics ; Retrospective Studies ; Young Adult
Chemical Substances	Receptors, Glycine
Language	English
Publishing date	2013-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awt207
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Article ; Online: Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes.

Oegema, Renske / Cushion, Thomas D / Phelps, Ian G / Chung, Seo-Kyung / Dempsey, Jennifer C / Collins, Sarah / Mullins, Jonathan G L / Dudding, Tracy / Gill, Harinder / Green, Andrew J / Dobyns, William B / Ishak, Gisele E / Rees, Mark I / Doherty, Dan

Human molecular genetics

2015 Volume 24, Issue 18, Page(s) 5313–5325

Abstract: Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients ... ...

Abstract	Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.
MeSH term(s)	Alleles ; Brain/pathology ; Cell Line ; Cerebellar Vermis/pathology ; Cerebellum/pathology ; Cohort Studies ; Female ; Genotype ; Humans ; Magnetic Resonance Imaging ; Male ; Microtubules/chemistry ; Microtubules/metabolism ; Models, Molecular ; Mutation ; Nervous System Malformations/diagnosis ; Nervous System Malformations/genetics ; Nervous System Malformations/pathology ; Phenotype ; Protein Conformation ; Protein Multimerization ; Structure-Activity Relationship ; Tubulin/chemistry ; Tubulin/genetics
Chemical Substances	TUBA1A protein, human ; TUBB2B protein, human ; TUBB3 protein, human ; Tubulin
Language	English
Publishing date	2015-09-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddv250
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Article ; Online: A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes.

Johnston, Ann J / Kang, Jing-Qiong / Shen, Wangzhen / Pickrell, William O / Cushion, Thomas D / Davies, Jeffrey S / Baer, Kristin / Mullins, Jonathan G L / Hammond, Carrie L / Chung, Seo-Kyung / Thomas, Rhys H / White, Cathy / Smith, Phil E M / Macdonald, Robert L / Rees, Mark I

Neurobiology of disease

2014 Volume 64, Page(s) 131–141

Abstract: Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence ... ...

Abstract	Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS+). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS+ and screened for variations in the γ2 subunit of the γ-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and extended behavioural presentation. The GABRG2(p.R136) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that γ2(p.R136) subunits were produced, but had reduced cell-surface and total expression. When γ2(p.R136) subunits were co-expressed with α1 and β2 subunits in HEK 293T cells, GABA-evoked currents were reduced. Furthermore, γ2(p.R136) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136) mutation extends the spectrum of GABRG2 mutations identified in GEFS+ and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism.
MeSH term(s)	Adult ; Animals ; COS Cells ; Cells, Cultured ; Cerebral Cortex/physiopathology ; Child ; Child, Preschool ; Chlorocebus aethiops ; Cohort Studies ; Epilepsy, Generalized/genetics ; Family ; Female ; HEK293 Cells ; Humans ; Infant ; Male ; Neurons/physiology ; PC12 Cells ; Phenotype ; Point Mutation ; Rats ; Receptors, GABA-A/genetics ; Receptors, GABA-A/metabolism ; Seizures, Febrile/genetics
Chemical Substances	GABRG2 protein, human ; Receptors, GABA-A
Language	English
Publishing date	2014-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2013.12.013
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Article ; Online: Overlapping cortical malformations and mutations in TUBB2B and TUBA1A.

Cushion, Thomas D / Dobyns, William B / Mullins, Jonathan G L / Stoodley, Neil / Chung, Seo-Kyung / Fry, Andrew E / Hehr, Ute / Gunny, Roxana / Aylsworth, Arthur S / Prabhakar, Prab / Uyanik, Gökhan / Rankin, Julia / Rees, Mark I / Pilz, Daniela T

Brain : a journal of neurology

2013 Volume 136, Issue Pt 2, Page(s) 536–548

Abstract: Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic ...

Abstract	Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α- and β-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.
MeSH term(s)	Adult ; Amino Acid Sequence ; Cerebral Cortex/abnormalities ; Cerebral Cortex/pathology ; Child ; Child, Preschool ; Female ; Genes, Overlapping/genetics ; Humans ; Infant, Newborn ; Lissencephaly/diagnosis ; Lissencephaly/genetics ; Male ; Malformations of Cortical Development/diagnosis ; Malformations of Cortical Development/genetics ; Molecular Sequence Data ; Mutation/genetics ; Tubulin/chemistry ; Tubulin/genetics
Chemical Substances	TUBA1A protein, human ; TUBB2B protein, human ; Tubulin
Language	English
Publishing date	2013-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/aws338
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