TUBA1A

protein-coding

tubulin alpha 1a, the group of Tubulins

Gene summary

Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to the mouse and rat Tuba1 genes. Northern blot studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q. Mutations in this gene cause lissencephaly type 3 (LIS3) - a neurological condition characterized by microcephaly, intellectual disability, and early-onset epilepsy caused by defective neuronal migration. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

MANE transcript

NM_006009.4

Inheritance

ClinVar variants

P:239U:92B:83

Top phenotype

Lissencephaly 3

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr12:49,184,686-49,189,324

External References & Databases

Ensembl (ENSG00000167552)

Transcript & Mutation Effects

hg38 • Region Span ~4.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tubulinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100153

Submitter: ClinGen

*TUBA1A* was first reported in relation to autosomal dominant tubulinopathy in 2007 (Keays et al., 2007 PMID: 17218254). Brain malformation disorders caused by mutations to *TUBA1A* and other neuronally expressed tubulin isotypes are collectively termed “tubulinopathies”, and lead to severe cortical abnormalities, mental retardation, and commonly epilepsy and paralysis. Patients containing *TUBA1A* mutations exhibit a wide variety of cerebral cortex malformation phenotypes including lissencephaly, pachygyria, microlissencephaly, and polymicrogyria (PMID: 29057214). This gene is curated under “tubulinopathy” (MONDO:0100153). Eighteen heterozygous variants (17 missense, 1 deletion) reported in eight publications have been included in this curation(PMID: 17218254, 17584854, 18728072, 21403111, 22948023, 26493046, 35837997, 35892608). Of these, 17 occurred de novo except for 2 sisters with tubulinopathy, born of consanguineous parents, who each had the same heterozygous mutation in the *TUBA1A* gene inherited their asymptomatic mother who showed somatic mosaicism (Jansen et al., 2011 PMID: 21403111). The presumed mechanism of disease is haploinsufficiency and/or dominant negative effect. *TUBA1A* mutations may lead to protein folding defects or heterodimer instability; or altered lattice interactions. Either of these defects may produce haploinsufficiency/loss of function consequences, resulting in fewer polymerization competent tubulin heterodimers available to form microtubules, or changes in microtubule dynamics (PMID: 29057214). Additionally, *TUBA1A* mutations may lead to mutant tubulin heterodimers that appropriately polymerize and cause toxic, gain of function consequences from within the microtubule lattice (PMID: 29057214). The maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by two mouse models, functional alteration, and expression data (PMID: 33137126, 35127710, 17584854). In summary, there is definitive evidence supporting the relationship between *TUBA1A* and autosomal dominant tubulinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Brain Malformations Gene Curation Expert Panel on the meeting date 11/16/ 2023 (SOP Version 9)

tubulinopathy-associated dysgyriaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018763

Submitter: Orphanet

lissencephaly due to TUBA1A mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012703

Submitter: Ambry Genetics

lissencephaly due to TUBA1A mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012703

Submitter: Labcorp Genetics (formerly Invitae)

congenital fibrosis of extraocular musclesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007614

Submitter: PanelApp Australia

lissencephaly due to TUBA1A mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012703

Submitter: PanelApp Australia

lissencephaly due to TUBA1A mutationDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012703

Submitter: G2P

lissencephaly due to TUBA1A mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012703

Submitter: Orphanet

Clinical Genomic Database (CGD)

Lissencephaly 3AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17218254; 17584854; 18728072; 18954413; 21403111; 22264709; 22633752; 22948023; 23317684; 23528852; 23361065

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBA1A variants in ClinVar

43 Conditions Cataloged

not providedTotal: 264

Lissencephaly due to TUBA1A mutationTotal: 151

TubulinopathyTotal: 113

not specifiedTotal: 49

TUBA1A-related disorderTotal: 47

Inborn genetic diseasesTotal: 27

Tubulinopathy-associated dysgyriaTotal: 9

LissencephalyTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006009.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				78 clinvar	4 clinvar	82
missense	62 clinvar	174 clinvar	85 clinvar	1 clinvar		322
nonsense		1 clinvar				1
start loss			1 clinvar			1
frameshift	1 clinvar	1 clinvar	3 clinvar			5
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	63	176	92	79	4	414

Highest pathogenic variant AF is 0.00000547451

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006009.4	RefSeq	NP_006000.2	4	MANE Select
ENST00000301071.12	Ensembl	ENSP00000301071.7	4	MANE Select
NM_001270399.2	RefSeq	NP_001257328.1	4	Standard
NM_001270400.2	RefSeq	NP_001257329.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tuba1a	Danio rerio	Structure: whole organism Quality: dead abnormal

Gene / Model

Organism

Observed Phenotype

tuba1a

Danio rerio

Structure: whole organism

Quality: dead

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Gap junction - Homo sapiens (human)
Pathogenic Escherichia coli infection - Homo sapiens (human)
Apoptosis - Homo sapiens (human)

Biological Process

G2/M transition of mitotic cell cycle
microtubule cytoskeleton organization
mitotic cell cycle
microtubule-based process
regulation of G2/M transition of mitotic cell cycle

Molecular Function

GTPase activity
structural molecule activity
structural constituent of cytoskeleton
protein binding
GTP binding

Cellular Component

nucleus
cytoplasm
cytosol
microtubule
cytoplasmic microtubule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301071
Coding exons: 4
Length: 4529
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125721
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.58	7	261	0.0268	0.0000155	2964
Missense (PolyPhen)		1	119.15	0.0083928		1437
Synonymous	-0.775	104	94.4	1.10	0.00000507	898
Loss of Function	3.34	1	15.0	0.0669	8.32e-7	178

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.;
Disease: DISEASE: Lissencephaly 3 (LIS3) [MIM:611603]: A classic type lissencephaly associated with psychomotor retardation and seizures. Features include agyria or pachygyria or laminar heterotopia, severe mental retardation, motor delay, variable presence of seizures, and abnormalities of corpus callosum, hippocampus, cerebellar vermis and brainstem. {ECO:0000269|PubMed:17584854, ECO:0000269|PubMed:25818041}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.278
RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.681