TUBA8

protein-coding

tubulin alpha 8, the group of Tubulins

Gene summary

This gene encodes a member of the alpha tubulin protein family. Alpha tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene are associated with polymicrogyria and optic nerve hypoplasia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

Previous symbols:

TUBAL2

MANE transcript

NM_018943.3

Inheritance

AD, AR

ClinVar variants

P:1U:211B:110

Top phenotype

Macrothrombocytopenia, isolated, 2, autosomal dominant; Polymicrogyria with optic nerve hypoplasia

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr22:18,110,100-18,146,683

External References & Databases

Ensembl (ENSG00000183785)

Transcript & Mutation Effects

hg38 • Region Span ~36.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

macrothrombocytopenia, isolated, 2, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030827

Submitter: PanelApp Australia

polymicrogyria with optic nerve hypoplasiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013172

Submitter: G2P

polymicrogyria with optic nerve hypoplasiaNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0013172

Submitter: PanelApp Australia

polymicrogyria with optic nerve hypoplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013172

Submitter: Orphanet

polymicrogyria with optic nerve hypoplasiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013172

Submitter: Labcorp Genetics (formerly Invitae)

polymicrogyria with optic nerve hypoplasiaNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0013172

Submitter: ClinGen

TUBA8 was first reported in relation to autosomal recessive Polymicrogyria with Optic Nerve Hypoplasia (PMGOH) in 2009 by Abdollahi et al. (PMID: 19896110). This condition is a highly uncommon disease with features of central nervous system anomalies associated with profound developmental delay, low muscle tone in infancy, seizures, and optic nerve hypoplasia. It is also associated with brain structural anomalies like extensive bilateral polymicrogyria and dysplastic or lack of corpus callosum. Three variants (frameshift, missense) that have been reported in 5 probands in 2 publications (PMIDs: 19896110, 29588952) are included in this curation. None of the variants were scored. The frameshift variant, truncating protein in exon 3 and associated with nonsense mediated decay, was found in a homozygous state in two consanguineous Pakistani families, not known to be related. The probands were found by Diggle et al., 2017 (PMID: 28388629) to also harbor a homozygous frameshift variant in SNAP29, which is associated with autosomal recessive CEDNIK Syndrome, a condition that has features of microcephaly with facial anomalies including elongation of the face, upward-slanting palpebral fissures, and mild hypertelorism. Additionally, in the Diggle et al., 2017 article, mice with a homozygous loss of function variant (associated with exon 3 skipping and nonsense mediated decay) did not have polymicrogyria. Another proband, who had compound heterozygous missense variants in trans in TUBA8, had epilepsy but no brain structural anomalies or optic nerve hypoplasia (Fung et al., 2017; PMID: 29588952). Mouse expression-level evidence, by Diggle et al., 2017, was not scored, because there were not significant differences in expression of TUBA8 within the brain between the homozygous mutant and wild-type mice. There is no other expression level evidence available. In summary, the evidence supporting the relationship between TUBA8 and autosomal recessive PMGOH has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role TUBA8 plays in this disease. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date October 10th, 2023 (SOP Version # 9).

Clinical Genomic Database (CGD)

Macrothrombocytopenia, isolated, 2, autosomal dominant; Polymicrogyria with optic nerve hypoplasiaAD/AR

Manifestation: Hematologic; Neurologic; Ophthalmologic

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: 19896110; 34704371

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBA8 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 330

not specifiedTotal: 86

TUBA8-related disorderTotal: 18

Polymicrogyria with optic nerve hypoplasiaTotal: 8

Macrothrombocytopenia, isolated, 2, autosomal dominantTotal: 6

Duane retraction syndromeTotal: 1

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018943.3. 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			1 clinvar	101 clinvar	2 clinvar	104
missense	1 clinvar		190 clinvar	6 clinvar	1 clinvar	198
nonsense			4 clinvar			4
start loss			1 clinvar			1
frameshift			12 clinvar			12
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	0	211	107	3	322

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018943.3	RefSeq	NP_061816.1	5	MANE Select
ENST00000330423.8	Ensembl	ENSP00000333326.3	5	MANE Select
NM_001193414.2	RefSeq	NP_001180343.1	4	Standard
ENST00000316027.10	Ensembl	ENSP00000318575.6	4	Standard

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

microtubule cytoskeleton organization
mitotic cell cycle
microtubule-based process

Molecular Function

GTPase activity
structural constituent of cytoskeleton
GTP binding

Cellular Component

cytoplasm
microtubule
microtubule cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330423
Coding exons: 5
Length: 36225
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.631	250	280	0.894	0.0000179	2956
Missense (PolyPhen)		145	161.8	0.89618		1760
Synonymous	0.160	111	113	0.981	0.00000766	899
Loss of Function	1.31	9	14.3	0.627	6.15e-7	179

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00049	0.00049	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000099	0.000098	rare
Other	0.00049	0.00049	rare

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: Cortical dysplasia, complex, with other brain malformations 8 (CDCBM8) [MIM:613180]: A disease characterized by extensive polymicrogyria, optic nerve hypoplasia, severe developmental delay, hypotonia, seizures, a dysplastic or absent corpus callosum and colpocephaly. Polymicrogyria is a malformation of the cortex in which the brain surface is irregular and characterized by an excessive number of small gyri with abnormal lamination. Polymicrogyria is a heterogeneous disorder, considered to be the result of postmigratory abnormal cortical organization. {ECO:0000269|PubMed:19896110}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.350

Intolerance Scores

LoFtool: 0.181
RVIS EVS: -0.29
RVIS percentile EVS: 33.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.954

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium