* 602529

TUBULIN, ALPHA-1A; TUBA1A


Alternative titles; symbols

TUBULIN, ALPHA, BRAIN-SPECIFIC
B-ALPHA-1
TUBA3


HGNC Approved Gene Symbol: TUBA1A

Cytogenetic location: 12q13.12     Genomic coordinates (GRCh38): 12:49,184,795-49,189,080 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q13.12 Lissencephaly 3 611603 AD 3

TEXT

Gene Family

Microtubules tend to be functionally distinct and are involved in mitosis, cell movement, intracellular movement, and other biologic processes. The main components of microtubules are different isoforms of alpha and beta tubulins, which are often cell-type specific.

Lewis and Cowan (1990) reviewed the alpha-tubulin gene family. In humans, this family consists of 15 to 20 dispersed genes, many of which are processed pseudogenes. The positions of the first 3 introns are identical between members of the human and rat gene families; in addition, some human alpha-tubulin genes have a fourth intron, also at an identical position. Within a vertebrate species, the genes can be distinguished by their 3-prime untranslated regions (UTRs). Since a large proportion of the diversity of alpha-tubulins is clustered at the C-terminal region and is conserved across species, alpha-tubulin genes can be classified based on homology of their encoded C-terminal motifs to those of mouse alpha-tubulin genes.


Nomenclature

See Khodiyar et al. (2007) for a revised nomenclature of the alpha-tubulin gene family.


Cloning and Expression

The b-alpha-1 gene, cloned from a human fetal brain cDNA library by Cowan et al. (1983), is the human counterpart of mouse M-alpha-1. By Northern blot analysis, Cowan et al. (1983) showed that b-alpha-1 mRNA is expressed only in brain. They found that the 3-prime UTR of b-alpha-1 is more than 80% homologous to the UTR of the rat brain alpha-tubulin gene, IL-alpha-T1.

Hall and Cowan (1985) screened a human genomic library with the 3-prime UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene. B-alpha-1 encodes a predicted 451-amino acid protein that is 100% identical to the rat homolog and differs by only 2 and 3 amino acids from the pig and chicken homologs, respectively. Furthermore, they observed that the first and largest intron of the b-alpha-1 gene is homologous to that of the rat gene. Northern blotting showed that b-alpha-1 expression was restricted to morphologically differentiated neurologic cells.

By Northern blot analysis and in situ hybridization, Miller et al. (1987) found that the rat homolog of b-alpha-1, which they called T-alpha-1, is expressed at high levels during the extension of neuronal processes.

Crabtree et al. (2001) cloned alpha-tubulin variants from a human retina cDNA library. One variant had the same sequence as the clone isolated by Cowan et al. (1983) from fetal brain, and the other had the same sequence as the brain-specific alpha-tubulin clone isolated by Hall and Cowan (1985), suggesting that this alpha-tubulin gene is expressed in both brain and retina.

Poirier et al. (2007) detected high expression of the TUBA1A gene in human fetal brain. Detailed study of mouse embryos showed expression in the cortex, hippocampus, cerebellum, brainstem, and rostral migratory stream. Tuba1a expression was decreased in most neurons at later postnatal stages and in adulthood.


Gene Structure

Hall and Cowan (1985) determined that the b-alpha-1 gene contains 4 exons and spans less than 4 kb.


Mapping

Scott (2001) mapped the TUBA1A gene to human chromosome 12 based on sequence similarity between the TUBA1A sequence (GenBank AF141347) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank AC016125 and GenBank AC010173).

Khodiyar et al. (2007) stated that the TUBA1A gene maps to human chromosome 12q13.12 and mouse chromosome 15F1.


Molecular Genetics

In 2 unrelated patients with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified 2 different de novo heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002). Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations (see, e.g., 602529.0003-602529.0005) in 6 additional patients with a wide spectrum of brain dysgenesis, ranging from agyria to laminar heterotopia. Retrospective examination of brain MRI showed defects in the cerebellum, hippocampus, corpus callosum, and brainstem. Patients who survived showed mental retardation, seizures, motor delay, and microcephaly. In general, gyral malformations were more severe in the posterior than anterior brain regions.

Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with lissencephaly who were negative for mutations in other known lissencephaly-associated genes. The phenotype ranged from the less severe perisylvian pachygyria to the more severe posteriorly predominant pachygyria, which was associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A mutations shared a common clinical phenotype consisting of congenital microcephaly, mental retardation and diplegia/tetraplegia.

Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations (see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545) mutation. Four of the 5 patients had congenital microcephaly, and all had dysgenesis of the corpus callosum, cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule.

Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in whom mutations in DCX and PAFAH1B1 had been excluded and identified novel and recurrent TUBA1A mutations in 1% of children with classic lissencephaly and in 30% of children with lissencephaly with cerebellar hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of the corpus callosum and cerebellar hypoplasia without lissencephaly. The authors demonstrated a wider spectrum of phenotypes than had been reported and suggested that lissencephaly-associated mutations of TUBA1A may operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins.

Tian et al. (2010) studied the effects of 9 disease-associated TUBA1A mutations on tubulin folding, heterodimer assembly, microtubule dynamics, and stability. The translational yield of each mutant protein varied across a continuum from an amount similar to that of wildtype for mutant L286F, to slightly reduced formation for mutants I188L (602529.0003), I238V, P263T (602529.0004), R402H (602529.0002) and S419L (602529.0005), to significantly diminished amounts for mutants V303G, L397P, and R402C. Studies of GTP-dependent polymerization and depolymerization indicated that all the disease-causing TUBA1A mutations were competent for assembly into microtubules in vitro. However, some of the mutant proteins showed defects in the tubulin heterodimer assembly pathway, with deficiencies in the production of intermediates. Mutants I188L, I238V, L397P and R402C all generated lower yields of intermediates compared to control TUBA1A; in addition, R402C showed a time-dependent decay of intermediates, indicating instability. Some of the mutant proteins (R264C, V303G, and L397P) also showed defective interaction with assembly chaperone protein TBCB (see, e.g., TBCA, 610058). Tests of heterodimer stability showed that P263T and V303G had reduced stability, whereas L397P and R402C were highly unstable. P263T expression resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, whereas the other mutant proteins did not show defects in microtubule growth. The findings demonstrated that different TUBA1A mutations result in a variety of tubulin defects, but also suggested that the mutations may cause compromised interactions with other interacting proteins essential for proper neuronal migration.

Aiken et al. (2019) found that expression of human TUBA1A R402C or R402H mutants in mouse brain disrupted cortical neuron migration. Analogous R402 mutant alpha-tubulins in yeast assembled into microtubules, but microtubule polymerization rates were lower and dynein function was perturbed. Impairment of dynein activity scaled with the expression level of the mutant alpha-tubulin in yeast, suggesting a dominant 'poisoning' mechanism.


Animal Model

Keays et al. (2007) reported a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex accompanied by impaired neuronal migration. Fine mapping and genomic screening identified an S140G mutation in the Tuba1a gene. Functional studies showed that the mutation resulted in decreased GTP binding and impaired tubulin heterodimer formation. However, heterodimers that did form were able to polymerize and were incorporated into the microtubule network of cultured cells. Abnormal neuronal migration was manifest as perturbations in layers II/III and IV of the visual, auditory, and somatosensory cortices, and a fractured pyramidal cell layer in the hippocampus. Behavioral studies showed that the mutant mice had impaired spatial working memory, reduced anxiety, and abnormal nesting, consistent with a hippocampal deficit. Keays et al. (2007) concluded that pathogenic mutations in the TUBA1A gene interferes with microtubule function, thus impairing neuronal migration.


ALLELIC VARIANTS ( 9 Selected Examples):

.0001 LISSENCEPHALY 3

TUBA1A, ARG264CYS
  
RCV000007486...

In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 790C-T transition in exon 4 of the TUBA1A gene, resulting in an arg264-to-cys (R264C) substitution in a loop between H8 and S7. The patient had microcephaly, pachygyria, an abnormally shaped corpus callosum, and hypoplasia of the cerebellar vermis and brainstem. Clinical features included severe mental retardation, mild motor delay, and absence of seizures. Poirier et al. (2007) reported another unrelated patient with a similar phenotype who carried the R264C mutation.

Bahi-Buisson et al. (2008) identified the R264C mutation in 2 additional unrelated patients with LIS3.


.0002 LISSENCEPHALY 3

TUBA1A, ARG402HIS
  
RCV000007487...

In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 1205G-A transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his (R402H) substitution at the beginning of the H11-H12 loop near the interface with beta-tubulin (191130). The patient had microcephaly, agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. Clinical features included profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant R402H performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins.


.0003 LISSENCEPHALY 3

TUBA1A, ILE188LEU
  
RCV000007488...

In a female patient with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a heterozygous de novo 562A-C transversion in the TUBA1A gene, resulting in an ile188-to-leu (I188L) substitution. She had microcephaly, laminar heterotopia, thin corpus callosum with partial agenesis, and hypoplasia of the brainstem and cerebellar vermis.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant I188L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins.


.0004 LISSENCEPHALY 3

TUBA1A, PRO263THR
  
RCV000007489...

In a 26-week-old fetus with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a de novo heterozygous 787C-A transversion in the TUBA1A gene, resulting in a pro263-to-thr (P263T) substitution. Postmortem examination showed agyria, agenesis of the corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant P263T showed reduced stability and resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, with a damping of the microtubule growth rate.


.0005 LISSENCEPHALY 3

TUBA1A, SER419LEU
  
RCV000007490...

In an 18-year-old man with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a de novo heterozygous 1256C-T transition in the TUBA1A gene, resulting in a ser419-to-leu (S419L) substitution. He had profound mental retardation, spastic tetraplegia, intractable seizures, and pachygyria.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant S419L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins.


.0006 LISSENCEPHALY 3

TUBA1A, LEU397PRO
  
RCV000007491...

In a 5.5-year-old boy with lissencephaly-3 (LIS3; 611603), Bahi-Buisson et al. (2008) identified a de novo heterozygous 1190T-C transition in the TUBA1A gene, resulting in a leu397-to-pro (L397P) substitution. The patient had microcephaly, spastic diplegia, and cognitive delay with few words acquired. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and posterior agenesis of the corpus callosum. There was also severe vermian dysplasia of the cerebellum. The mutation was not identified in 360 control individuals.


.0007 LISSENCEPHALY 3

TUBA1A, ARG422CYS
  
RCV000007492...

In a 4.5-year-old girl with lissencephaly-3 (LIS3; 611603), Bahi-Buisson et al. (2008) identified a de novo heterozygous 1264C-T transition in the TUBA1A gene, resulting in an arg422-to-cys (R422C) substitution. The patient had microcephaly, spastic diplegia, and could speak only in short sentences. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and mild hypoplasia of the corpus callosum. There was also mild vermian hypoplasia of the cerebellum. The mutation was not identified in 360 control individuals.


.0008 LISSENCEPHALY 3

TUBA1A, ARG422HIS
  
RCV000007493...

In 2 unrelated patients with lissencephaly-3 (LIS3; 611603), Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his (R422H) substitution. In addition to the classic features of microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum and cerebellum, both patients had subtle evidence of subcortical band heterotopia.


.0009 LISSENCEPHALY 3

TUBA1A, ILE5LEU
  
RCV000023197...

In 2 sisters, born of consanguineous Moroccan parents, with lissencephaly-3 (LIS3; 611603), Jansen et al. (2011) identified a heterozygous 13A-C transversion in exon 2 of the TUBA1A gene, resulting in an ile5-to-leu (I5L) substitution. The girls had developmental delay, spastic diplegia, and ataxia; one had seizures. Brain MRI showed perisylvian polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with a hooked aspect of the right frontal horn due to abnormally shaped basal ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had optic nerve hypoplasia and mild vermian hypoplasia. The clinically asymptomatic mother was found to be somatic mosaic for the mutation, which was detected in 5.6% of DNA in peripheral blood. Her brain MRI showed a thin corpus callosum, hypoplasia of the superior vermis, and a thin medulla. The report indicated that rare familial recurrence of LIS3 can occur.


REFERENCES

  1. Aiken, J., Moore, J. K., Bates, E. A. TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity. Hum. Molec. Genet. 28: 1227-1243, 2019. [PubMed: 30517687, images, related citations] [Full Text]

  2. Bahi-Buisson, N., Poirier, K., Boddaert, N., Saillour, Y., Castelnau, L., Philip, N., Buyse, G., Villard, L., Joriot, S., Marret, S., Bourgeois, M., Van Esch, H., Lagae, L., Amiel, J., Hertz-Pannier, L., Roubertie, A., Rivier, F., Pinard, J. M., Beldjord, C., Chelly, J. Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations. J. Med. Genet. 45: 647-653, 2008. [PubMed: 18728072, related citations] [Full Text]

  3. Cowan, N. J., Dobner, P. R., Fuchs, E. V., Cleveland, D. W. Expression of human alpha-tubulin genes: interspecies conservation of 3-prime untranslated regions. Molec. Cell. Biol. 3: 1738-1745, 1983. [PubMed: 6646120, related citations] [Full Text]

  4. Crabtree, D. V., Ojima, I., Geng, X., Adler, A. J. Tubulins in the primate retina: evidence that xanthophylls may be endogenous ligands for the paclitaxel-binding site. Bioorg. Med. Chem. 9: 1967-1976, 2001. [PubMed: 11504633, related citations] [Full Text]

  5. Hall, J. L., Cowan, N. J. Structural features and restricted expression of a human alpha-tubulin gene. Nucleic Acids Res. 13: 207-223, 1985. [PubMed: 3839072, related citations] [Full Text]

  6. Jansen, A. C., Oostra, A., Desprechins, B., De Vlaeminck, Y., Verhelst, H., Regal, L., Verloo, P., Bockaert, N., Keymolen, K., Seneca, S., De Meirleir, L., Lissens, W. TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria. Neurology 76: 988-992, 2011. [PubMed: 21403111, related citations] [Full Text]

  7. Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128: 45-57, 2007. [PubMed: 17218254, images, related citations] [Full Text]

  8. Khodiyar, V. K., Maltais, L. J., Ruef, B. J., Sneddon, K. M. B., Smith, J. R., Shimoyama, M., Cabral, F., Dumontet, C., Dutcher, S. K., Harvey, R. J., Lafanechere, L., Murray, J. M., Nogales, E., Piquemal, D., Stanchi, F., Povey, S., Lovering, R. C. A revised nomenclature for the human and rodent alpha-tubulin gene family. Genomics 90: 285-289, 2007. Note: Erratum: Genomics 93: 397 only, 2009. [PubMed: 17543498, related citations] [Full Text]

  9. Kumar, R. A., Pilz, D. T., Babatz, T. D., Cushion, T. D., Harvey, K., Topf, M., Yates, L., Robb, S., Uyanik, G., Mancini, G. M. S., Rees, M. I., Harvey, R. J., Dobyns, W. B. TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins. Hum. Molec. Genet. 19: 2817-2827, 2010. [PubMed: 20466733, images, related citations] [Full Text]

  10. Lewis, S. A., Cowan, N. J. Tubulin genes: structure, expression, and regulation.In: Avila, J. (ed.) : Microtubule proteins. Boca Raton: CRC Press, Inc. 1990. Pp. 37-66.

  11. Miller, F. D., Naus, C. C. G., Durand, M., Bloom, F. E., Milner, R. J. Isotypes of alpha-tubulin are differentially regulated during neuronal maturation. J. Cell Biol. 105: 3065-3073, 1987. [PubMed: 3693406, related citations] [Full Text]

  12. Morris-Rosendahl, D. J., Najm, J., Lachmeijer, A. M. A., Sztriha, L., Martins, M., Kuechler, A., Haug, V., Zeschnigk, C., Martin, P., Santos, M., Vasconcelos, C., Omran, H., Kraus, U., Van der Knaap, M. S., Schuierer, G., Kutsche, K., Uyanik, G. Refining the phenotype of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin. Genet. 74: 425-433, 2008. [PubMed: 18954413, related citations] [Full Text]

  13. Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). Hum. Mutat. 28: 1055-1064, 2007. [PubMed: 17584854, related citations] [Full Text]

  14. Scott, A. F. Personal Communication. Baltimore, Md. 10/3/2001.

  15. Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J. Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway. Hum. Molec. Genet. 19: 3599-3613, 2010. [PubMed: 20603323, images, related citations] [Full Text]


Bao Lige - updated : 09/26/2019
George E. Tiller - updated : 9/5/2013
Cassandra L. Kniffin - updated : 4/18/2012
Cassandra L. Kniffin - updated : 3/3/2009
Cassandra L. Kniffin - updated : 2/12/2009
Cassandra L. Kniffin - updated : 11/19/2007
Patricia A. Hartz - updated : 12/21/2004
Alan F. Scott - updated : 10/3/2001
Creation Date:
Rebekah S. Rasooly : 4/16/1998
carol : 10/14/2021
mgross : 09/26/2019
mgross : 09/26/2019
carol : 06/04/2019
carol : 03/11/2015
alopez : 9/5/2013
terry : 11/28/2012
carol : 5/3/2012
ckniffin : 4/18/2012
alopez : 8/18/2011
alopez : 8/18/2011
ckniffin : 8/3/2011
wwang : 3/6/2009
ckniffin : 3/3/2009
wwang : 2/20/2009
ckniffin : 2/12/2009
wwang : 12/14/2007
ckniffin : 11/19/2007
carol : 9/13/2007
carol : 9/11/2007
alopez : 2/8/2007
alopez : 2/8/2007
mgross : 1/12/2005
terry : 12/21/2004
joanna : 10/3/2001
alopez : 6/18/1999
psherman : 4/20/1998
psherman : 4/16/1998

* 602529

TUBULIN, ALPHA-1A; TUBA1A


Alternative titles; symbols

TUBULIN, ALPHA, BRAIN-SPECIFIC
B-ALPHA-1
TUBA3


HGNC Approved Gene Symbol: TUBA1A

SNOMEDCT: 1003444000;  


Cytogenetic location: 12q13.12     Genomic coordinates (GRCh38): 12:49,184,795-49,189,080 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q13.12 Lissencephaly 3 611603 Autosomal dominant 3

TEXT

Gene Family

Microtubules tend to be functionally distinct and are involved in mitosis, cell movement, intracellular movement, and other biologic processes. The main components of microtubules are different isoforms of alpha and beta tubulins, which are often cell-type specific.

Lewis and Cowan (1990) reviewed the alpha-tubulin gene family. In humans, this family consists of 15 to 20 dispersed genes, many of which are processed pseudogenes. The positions of the first 3 introns are identical between members of the human and rat gene families; in addition, some human alpha-tubulin genes have a fourth intron, also at an identical position. Within a vertebrate species, the genes can be distinguished by their 3-prime untranslated regions (UTRs). Since a large proportion of the diversity of alpha-tubulins is clustered at the C-terminal region and is conserved across species, alpha-tubulin genes can be classified based on homology of their encoded C-terminal motifs to those of mouse alpha-tubulin genes.


Nomenclature

See Khodiyar et al. (2007) for a revised nomenclature of the alpha-tubulin gene family.


Cloning and Expression

The b-alpha-1 gene, cloned from a human fetal brain cDNA library by Cowan et al. (1983), is the human counterpart of mouse M-alpha-1. By Northern blot analysis, Cowan et al. (1983) showed that b-alpha-1 mRNA is expressed only in brain. They found that the 3-prime UTR of b-alpha-1 is more than 80% homologous to the UTR of the rat brain alpha-tubulin gene, IL-alpha-T1.

Hall and Cowan (1985) screened a human genomic library with the 3-prime UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene. B-alpha-1 encodes a predicted 451-amino acid protein that is 100% identical to the rat homolog and differs by only 2 and 3 amino acids from the pig and chicken homologs, respectively. Furthermore, they observed that the first and largest intron of the b-alpha-1 gene is homologous to that of the rat gene. Northern blotting showed that b-alpha-1 expression was restricted to morphologically differentiated neurologic cells.

By Northern blot analysis and in situ hybridization, Miller et al. (1987) found that the rat homolog of b-alpha-1, which they called T-alpha-1, is expressed at high levels during the extension of neuronal processes.

Crabtree et al. (2001) cloned alpha-tubulin variants from a human retina cDNA library. One variant had the same sequence as the clone isolated by Cowan et al. (1983) from fetal brain, and the other had the same sequence as the brain-specific alpha-tubulin clone isolated by Hall and Cowan (1985), suggesting that this alpha-tubulin gene is expressed in both brain and retina.

Poirier et al. (2007) detected high expression of the TUBA1A gene in human fetal brain. Detailed study of mouse embryos showed expression in the cortex, hippocampus, cerebellum, brainstem, and rostral migratory stream. Tuba1a expression was decreased in most neurons at later postnatal stages and in adulthood.


Gene Structure

Hall and Cowan (1985) determined that the b-alpha-1 gene contains 4 exons and spans less than 4 kb.


Mapping

Scott (2001) mapped the TUBA1A gene to human chromosome 12 based on sequence similarity between the TUBA1A sequence (GenBank AF141347) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank AC016125 and GenBank AC010173).

Khodiyar et al. (2007) stated that the TUBA1A gene maps to human chromosome 12q13.12 and mouse chromosome 15F1.


Molecular Genetics

In 2 unrelated patients with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified 2 different de novo heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002). Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations (see, e.g., 602529.0003-602529.0005) in 6 additional patients with a wide spectrum of brain dysgenesis, ranging from agyria to laminar heterotopia. Retrospective examination of brain MRI showed defects in the cerebellum, hippocampus, corpus callosum, and brainstem. Patients who survived showed mental retardation, seizures, motor delay, and microcephaly. In general, gyral malformations were more severe in the posterior than anterior brain regions.

Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with lissencephaly who were negative for mutations in other known lissencephaly-associated genes. The phenotype ranged from the less severe perisylvian pachygyria to the more severe posteriorly predominant pachygyria, which was associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A mutations shared a common clinical phenotype consisting of congenital microcephaly, mental retardation and diplegia/tetraplegia.

Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations (see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545) mutation. Four of the 5 patients had congenital microcephaly, and all had dysgenesis of the corpus callosum, cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule.

Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in whom mutations in DCX and PAFAH1B1 had been excluded and identified novel and recurrent TUBA1A mutations in 1% of children with classic lissencephaly and in 30% of children with lissencephaly with cerebellar hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of the corpus callosum and cerebellar hypoplasia without lissencephaly. The authors demonstrated a wider spectrum of phenotypes than had been reported and suggested that lissencephaly-associated mutations of TUBA1A may operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins.

Tian et al. (2010) studied the effects of 9 disease-associated TUBA1A mutations on tubulin folding, heterodimer assembly, microtubule dynamics, and stability. The translational yield of each mutant protein varied across a continuum from an amount similar to that of wildtype for mutant L286F, to slightly reduced formation for mutants I188L (602529.0003), I238V, P263T (602529.0004), R402H (602529.0002) and S419L (602529.0005), to significantly diminished amounts for mutants V303G, L397P, and R402C. Studies of GTP-dependent polymerization and depolymerization indicated that all the disease-causing TUBA1A mutations were competent for assembly into microtubules in vitro. However, some of the mutant proteins showed defects in the tubulin heterodimer assembly pathway, with deficiencies in the production of intermediates. Mutants I188L, I238V, L397P and R402C all generated lower yields of intermediates compared to control TUBA1A; in addition, R402C showed a time-dependent decay of intermediates, indicating instability. Some of the mutant proteins (R264C, V303G, and L397P) also showed defective interaction with assembly chaperone protein TBCB (see, e.g., TBCA, 610058). Tests of heterodimer stability showed that P263T and V303G had reduced stability, whereas L397P and R402C were highly unstable. P263T expression resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, whereas the other mutant proteins did not show defects in microtubule growth. The findings demonstrated that different TUBA1A mutations result in a variety of tubulin defects, but also suggested that the mutations may cause compromised interactions with other interacting proteins essential for proper neuronal migration.

Aiken et al. (2019) found that expression of human TUBA1A R402C or R402H mutants in mouse brain disrupted cortical neuron migration. Analogous R402 mutant alpha-tubulins in yeast assembled into microtubules, but microtubule polymerization rates were lower and dynein function was perturbed. Impairment of dynein activity scaled with the expression level of the mutant alpha-tubulin in yeast, suggesting a dominant 'poisoning' mechanism.


Animal Model

Keays et al. (2007) reported a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex accompanied by impaired neuronal migration. Fine mapping and genomic screening identified an S140G mutation in the Tuba1a gene. Functional studies showed that the mutation resulted in decreased GTP binding and impaired tubulin heterodimer formation. However, heterodimers that did form were able to polymerize and were incorporated into the microtubule network of cultured cells. Abnormal neuronal migration was manifest as perturbations in layers II/III and IV of the visual, auditory, and somatosensory cortices, and a fractured pyramidal cell layer in the hippocampus. Behavioral studies showed that the mutant mice had impaired spatial working memory, reduced anxiety, and abnormal nesting, consistent with a hippocampal deficit. Keays et al. (2007) concluded that pathogenic mutations in the TUBA1A gene interferes with microtubule function, thus impairing neuronal migration.


ALLELIC VARIANTS 9 Selected Examples):

.0001   LISSENCEPHALY 3

TUBA1A, ARG264CYS
SNP: rs137853043, ClinVar: RCV000007486, RCV000622693, RCV000767404, RCV001291302, RCV001564937

In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 790C-T transition in exon 4 of the TUBA1A gene, resulting in an arg264-to-cys (R264C) substitution in a loop between H8 and S7. The patient had microcephaly, pachygyria, an abnormally shaped corpus callosum, and hypoplasia of the cerebellar vermis and brainstem. Clinical features included severe mental retardation, mild motor delay, and absence of seizures. Poirier et al. (2007) reported another unrelated patient with a similar phenotype who carried the R264C mutation.

Bahi-Buisson et al. (2008) identified the R264C mutation in 2 additional unrelated patients with LIS3.


.0002   LISSENCEPHALY 3

TUBA1A, ARG402HIS
SNP: rs137853044, ClinVar: RCV000007487, RCV000767403, RCV001091238, RCV001291299, RCV001801361

In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 1205G-A transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his (R402H) substitution at the beginning of the H11-H12 loop near the interface with beta-tubulin (191130). The patient had microcephaly, agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. Clinical features included profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant R402H performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins.


.0003   LISSENCEPHALY 3

TUBA1A, ILE188LEU
SNP: rs137853045, ClinVar: RCV000007488, RCV000767405

In a female patient with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a heterozygous de novo 562A-C transversion in the TUBA1A gene, resulting in an ile188-to-leu (I188L) substitution. She had microcephaly, laminar heterotopia, thin corpus callosum with partial agenesis, and hypoplasia of the brainstem and cerebellar vermis.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant I188L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins.


.0004   LISSENCEPHALY 3

TUBA1A, PRO263THR
SNP: rs137853046, ClinVar: RCV000007489, RCV000767429

In a 26-week-old fetus with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a de novo heterozygous 787C-A transversion in the TUBA1A gene, resulting in a pro263-to-thr (P263T) substitution. Postmortem examination showed agyria, agenesis of the corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant P263T showed reduced stability and resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, with a damping of the microtubule growth rate.


.0005   LISSENCEPHALY 3

TUBA1A, SER419LEU
SNP: rs137853047, ClinVar: RCV000007490, RCV000767406, RCV001815163

In an 18-year-old man with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a de novo heterozygous 1256C-T transition in the TUBA1A gene, resulting in a ser419-to-leu (S419L) substitution. He had profound mental retardation, spastic tetraplegia, intractable seizures, and pachygyria.

By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant S419L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins.


.0006   LISSENCEPHALY 3

TUBA1A, LEU397PRO
SNP: rs137853048, ClinVar: RCV000007491, RCV000767468

In a 5.5-year-old boy with lissencephaly-3 (LIS3; 611603), Bahi-Buisson et al. (2008) identified a de novo heterozygous 1190T-C transition in the TUBA1A gene, resulting in a leu397-to-pro (L397P) substitution. The patient had microcephaly, spastic diplegia, and cognitive delay with few words acquired. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and posterior agenesis of the corpus callosum. There was also severe vermian dysplasia of the cerebellum. The mutation was not identified in 360 control individuals.


.0007   LISSENCEPHALY 3

TUBA1A, ARG422CYS
SNP: rs137853049, ClinVar: RCV000007492, RCV000432377, RCV000622854, RCV000767469

In a 4.5-year-old girl with lissencephaly-3 (LIS3; 611603), Bahi-Buisson et al. (2008) identified a de novo heterozygous 1264C-T transition in the TUBA1A gene, resulting in an arg422-to-cys (R422C) substitution. The patient had microcephaly, spastic diplegia, and could speak only in short sentences. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and mild hypoplasia of the corpus callosum. There was also mild vermian hypoplasia of the cerebellum. The mutation was not identified in 360 control individuals.


.0008   LISSENCEPHALY 3

TUBA1A, ARG422HIS
SNP: rs137853050, ClinVar: RCV000007493, RCV000255074, RCV000767410, RCV001291201

In 2 unrelated patients with lissencephaly-3 (LIS3; 611603), Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his (R422H) substitution. In addition to the classic features of microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum and cerebellum, both patients had subtle evidence of subcortical band heterotopia.


.0009   LISSENCEPHALY 3

TUBA1A, ILE5LEU
SNP: rs387906840, ClinVar: RCV000023197, RCV000767414

In 2 sisters, born of consanguineous Moroccan parents, with lissencephaly-3 (LIS3; 611603), Jansen et al. (2011) identified a heterozygous 13A-C transversion in exon 2 of the TUBA1A gene, resulting in an ile5-to-leu (I5L) substitution. The girls had developmental delay, spastic diplegia, and ataxia; one had seizures. Brain MRI showed perisylvian polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with a hooked aspect of the right frontal horn due to abnormally shaped basal ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had optic nerve hypoplasia and mild vermian hypoplasia. The clinically asymptomatic mother was found to be somatic mosaic for the mutation, which was detected in 5.6% of DNA in peripheral blood. Her brain MRI showed a thin corpus callosum, hypoplasia of the superior vermis, and a thin medulla. The report indicated that rare familial recurrence of LIS3 can occur.


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Contributors:
Bao Lige - updated : 09/26/2019
George E. Tiller - updated : 9/5/2013
Cassandra L. Kniffin - updated : 4/18/2012
Cassandra L. Kniffin - updated : 3/3/2009
Cassandra L. Kniffin - updated : 2/12/2009
Cassandra L. Kniffin - updated : 11/19/2007
Patricia A. Hartz - updated : 12/21/2004
Alan F. Scott - updated : 10/3/2001

Creation Date:
Rebekah S. Rasooly : 4/16/1998

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