Alternative titles; symbols
HGNC Approved Gene Symbol: TUBB4A
SNOMEDCT: 724283004; ICD10CM: G23.3;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:6,494,319-6,502,848 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Dystonia 4, torsion, autosomal dominant | 128101 | Autosomal dominant | 3 |
| Leukodystrophy, hypomyelinating, 6 | 612438 | Autosomal dominant | 3 |
Microtubules are dynamic polymeric structures consisting of heterodimers of alpha-tubulins (see 602529) and beta-tubulins that are continuously incorporated and released. Microtubules are an essential component of the cytoskeleton that function in mitosis, intracellular transport, neuron morphology, and ciliary and flagellar motility (Leandro-Garcia et al., 2010). The TUBB4A gene encodes a brain-specific member of the beta-tubulin family that is most highly expressed in the cerebellum, putamen, and white matter (summary by Kancheva et al., 2015).
Hall et al. (1983) identified the TUBB4A gene, which they designated 5-beta. The 5-beta gene was expressed as a 2.6-kb transcript on Northern blots of HeLa cell mRNA. Lee et al. (1984) reported that the 5-beta sequence encodes a predicted 445-amino acid protein. Using Northern analysis, they determined that 5-beta is expressed in fetal brain, but not in cell lines derived from various other tissues. Lewis and Cowan (1990) stated that the mouse homolog of 5-beta, M-beta-4, is expressed specifically in brain.
Using database analysis, Leandro-Garcia et al. (2010) identified 8 major beta-tubulins, including TUBB4A, which they called TUBB4. Quantitative RT-PCR of 21 normal human tissues detected high TUBB4A expression in brain and much lower expression in testis. Little to no expression was detected in other tissues examined. TUBB4A was the major beta-tubulin isotype in brain, where it represented 46% of all beta-tubulins.
In human brain, Hersheson et al. (2013) found highest expression of the TUBB4A gene in the cerebellum, followed by putamen and white matter. The thalamus showed the lowest expression of all brain regions studied. Expression of TUBB4A in other body tissues was very low except for moderate expression in the testes.
Hartz (2013) mapped the TUBB4A gene to chromosome 19p13.3 based on an alignment of the TUBB4A sequence (GenBank BC006570) with the genomic sequence (GRCh37).
Dystonia 4
In affected members of a large multigenerational family of English and Australian origin with autosomal dominant dystonia-4 (DYT4; 128101) (Parker, 1985), Hersheson et al. (2013) identified a heterozygous mutation in the TUBB4A gene (R2G; 602662.0001), resulting in an arg2-to-gly (R2G) substitution at a highly conserved residue in the autoregulatory MREI domain. The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with the disorder in the family. Previous site-directed mutagenesis studies by Yen et al. (1988) had shown that mutations in the MREI domain, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis.
Independently and simultaneously, Lohmann et al. (2013) identified a heterozygous R2G mutation in the TUBB4A gene in the family with DYT4 originally reported by Parker (1985). The mutation was found by genomewide linkage analysis and genome sequencing in 2 family members. Cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls. Screening of the TUBB4A gene in 394 unrelated patients with dystonia revealed a different missense variant (A271T; 602662.0003) in a woman with onset of spasmodic dysphonia at age 60 years. Functional studies of the A271T variant were not performed.
Using high-resolution melting and Sanger sequencing, Vemula et al. (2014) did not find any pathogenic variants in the TUBB4A gene in 575 adult individuals with primary laryngeal, segmental, or generalized dystonia. The patients were mainly Caucasians of European descent. The findings suggested that variation in TUBB4A is not a significant cause of primary dystonia.
By next-generation sequencing with a dystonia gene panel or whole-exome sequencing in 11 patients from 4 families with DYT4, Bally et al. (2021) identified 4 novel heterozygous missense variants in the TUBB4A gene (D295N, R46M, Q424H, and R121W). Variants segregated with disease in 3 of the families, with evidence for incomplete penetrance in 2; in the fourth family, 1 affected and 4 unaffected members carried the variant (D295N). All variants changed highly conserved amino acids. No functional studies were performed, but all variants were predicted to be deleterious by in silico analysis. All were confirmed by Sanger sequencing, and none was seen in population databases.
Hypomyelinating Leukodystrophy 6
In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; 612438), Simons et al. (2013) identified the same de novo heterozygous mutation in the TUBB4A gene (D249N; 602662.0002). Two affected sibs inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed by motor deterioration and extrapyramidal signs. Six patients had cognitive decline and 2 had mild intellectual disability, but 3 had normal cognitive development. All patients except 1 had some type of speech delay and dysarthria.
In a 9-year-old boy with an attenuated form of HLD6, Blumkin et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (E410K; 602662.0004). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.
In a 4-year-old girl with HLD6, Purnell et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (R156L; 602662.0005). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.
In 8 unrelated Japanese patients with HLD6, Miyatake et al. (2014) identified heterozygous missense mutations in the TUBB4A gene (see, e.g., 602662.0002; 602662.0004; 602662.0006-602662.0007). The mutations were found by whole-exome sequencing and occurred de novo in all cases with available parental samples. Structural modeling suggested that the mutations could affect microtubule assembly, structure, or interaction with other proteins, but functional studies were not performed.
In affected members of a large multigenerational family of English and Australian origin with autosomal dominant dystonia-4 (DYT4; 128101) (Parker, 1985), Hersheson et al. (2013) identified a heterozygous c.4C-G transversion in exon 1 of the TUBB4A gene, resulting in an arg2-to-gly (R2G) substitution at a highly conserved residue in the autoregulatory MREI domain. The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with the disorder in the family. Previous site-directed mutagenesis studies by Yen et al. (1988) had shown that mutations in the MREI domain, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis.
Independently and simultaneously, Lohmann et al. (2013) identified a heterozygous R2G mutation in the TUBB4A gene in affected members of the family with DYT4 originally reported by Parker (1985). The mutation was found by genomewide linkage analysis combined with genome sequencing in 2 family members. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in 1,000 control chromosomes or in the Exome Variant Server database. Primary cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls, suggesting that the pathogenesis involved reduced levels of TUBB4A.
In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; 612438), Simons et al. (2013) identified a de novo heterozygous c.745G-A transition in the TUBB4A gene, resulting in an asp249-to-asn (D249N) substitution at a highly conserved residue in the T7 loop, which interacts with the GTP nucleotide bound to the N-site of the alpha-tubulin and is important for the longitudinal interaction between tubulins. Two sibs with the disorder inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed motor deterioration and extrapyramidal signs. Six patients had cognitive decline, 2 had mild intellectual disability, and 3 had normal cognitive development. All patients except 1 had some sort of speech delay and dysarthria. Simons et al. (2013) noted that the D249N substitution has been identified in other beta-tubulins as being pathogenic: in the Tubb1 gene (612901) in Cavalier King Charles Spaniel dogs with inherited macrothrombocytopenia (Davis et al., 2008), and in a beta-tubulin gene in C. elegans with loss of touch sensitivity (Savage et al., 1994).
Miyatake et al. (2014) identified the D249N mutation in 2 unrelated Japanese patients with HLD6, 1 of whom had previously been reported by Wakusawa et al. (2006). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The mutation occurred de novo in 1 patient and was absent from the mother's DNA in the second patient; paternal DNA for the second patient was not available. The D249N substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed.
In a 71-year-old woman with torsion dystonia (DYT4; 128101), Lohmann et al. (2013) identified a heterozygous change in the TUBB4A gene, resulting in an ala271-to-thr (A271T) substitution. The patient was ascertained from a cohort of 394 unrelated patients with dystonia who underwent screening for TUBB4A mutations. The patient had onset of spasmodic dysphonia and oromandibular dystonia and dyskinesia at age 60 years. Her mother had had dyskinesia around the mouth from age 70 years, and died at age 76; DNA from the mother was not available. Functional studies of the A271T variant were not performed.
In a 9-year-old boy with a slowly progressive form of hypomyelinating leukodystrophy-6 (HLD6; 612438), Blumkin et al. (2014) identified a de novo heterozygous c.1218G-A transition in the TUBB4A gene, resulting in a glu410-to-lys (E410K) substitution at a highly conserved residue in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed.
In 2 unrelated Japanese males with a protracted form of HLD6, Miyatake et al. (2014) identified a de novo heterozygous E410K substitution in the TUBB4A gene, which they stated resulted from a c.1228G-A transition. The patients were previously reported by Sasaki et al. (2009) as patients 2 and 3. The mutations, which were found by whole-exome sequencing, were not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The affected residue is located on the exposed outer surface that mediates interactions with motor proteins and/or microtubule-associated proteins and is crucial for the kinesin microtubule interaction. Functional studies of the variant were not performed.
In a 4-year-old girl with hypomyelinating leukodystrophy-6 (HLD6; 612438), Purnell et al. (2014) identified a de novo heterozygous c.467G-T transversion in exon 4 of the TUBB4A gene, resulting in an arg156-to-leu (R156L) substitution at a highly conserved residue in the alpha-helix-4 domain. The mutation was found by whole-exome sequencing; functional studies were not performed.
In a 15-year-old Japanese girl with hypomyelinating leukodystrophy-6 (HLD6; 612438), Miyatake et al. (2014) identified a heterozygous c.5G-A transition in the TUBB4A gene, resulting in an arg2-to-gln (R2Q) substitution at a highly conserved residue in the MREI motif involved in autoregulatory mechanisms for beta-tubulin stability. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Parental DNA was not available. Structural modeling showed that the R2Q substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. The patient had a severe disorder, with onset of symptoms at 1.5 months of age. She had severe mental retardation with no head control, spasticity, rigidity, choreoathetosis, and dystonia. Brain MRI showed hypomyelination and atrophy of the cerebellum, basal ganglia, and corpus callosum. Miyatake et al. (2014) noted that a mutation at the same residue (R2G; 602662.0001) had been reported in a single large family with a much milder and different phenotype (DYT4; 128101), and Miyatake et al. (2014) suggested that the large DYT4 family may have another modifying factor that protects against white matter abnormalities.
In a 4-year-old Japanese boy with hypomyelinating leukodystrophy-6 (HLD6; 612438), Miyatake et al. (2014) identified a de novo heterozygous c.533C-G transversion in the TUBB4A gene, resulting in a thr178-to-arg (T178R) substitution at a highly conserved residue at a longitudinal interheterodimer interface, suggesting that the mutation may affect the tubulin dimerization process. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Functional studies were not performed.
In 5 sibs with hypomyelinating leukodystrophy-6 (HLD6; 612438), born of consanguineous Roma Gypsy parents from Bulgaria, Kancheva et al. (2015) identified a heterozygous c.568C-T transition (c.568C-T, NM_006087.1) in the TUBB4A gene, resulting in a his190-to-tyr (H190Y) substitution at a conserved residue in the H5 helix at the interface involved in contacts between microtubule protofilaments. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was also found in the mosaic state in the unaffected mother (10% of her blood cells carried the mutant allele). The variant was not found in 72 ethnically matched controls. Functional studies of the variant were not performed. The patients presented with early-onset complicated spastic paraplegia without basal ganglia involvement, dystonia, or cognitive dysfunction.
Bally, J. F., Camargos, S., Oliveira Dos Santos, C., Kern, D. S., Lee, T., Pereira da Silva-Junior, F., Puga, R. D., Cardoso, F., Barbosa, E. R., Yadav, R., Ozelius, L. J., de Carvalho Aguiar, P., Lang, A. E. DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations. Neurology 96: e1887-e1897, 2021. [PubMed: 32943487] [Full Text: https://doi.org/10.1212/WNL.0000000000010882]
Blumkin, L., Halevy, A., Ben-Ami-Raichman, D., Dahari, D., Haviv, A., Sarit, C., Lev, D., van der Knaap, M. S., Lerman-Sagie, T., Leshinsky-Silver, E. Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene. Neurogenetics 15: 107-113, 2014. Note: Erratum: Neurogenetics 15: 115 only, 2014. [PubMed: 24526230] [Full Text: https://doi.org/10.1007/s10048-014-0392-2]
Davis, B., Toivio-Kinnucan, M., Schuller, S., Boudreaux, M. K. Mutation in beta-1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels. J. Vet. Intern. Med. 22: 540-545, 2008. [PubMed: 18466252] [Full Text: https://doi.org/10.1111/j.1939-1676.2008.0085.x]
Hall, J. L., Dudley, L., Dobner, P. R., Lewis, S. A., Cowan, N. J. Identification of two human beta-tubulin isotypes. Molec. Cell. Biol. 3: 854-862, 1983. [PubMed: 6865944] [Full Text: https://doi.org/10.1128/mcb.3.5.854-862.1983]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/28/2013.
Hersheson, J., Mencacci, N. E., Davis, M., MacDonald, N., Trabzuni, D., Ryten, M., Pittman, A., Paudel, R., Kara, E., Fawcett, K., Plagnol, V., Bhatia, K. P., Medlar, A. J., Stanescu, H. C., Hardy, J., Kleta, R., Wood, N. W., Houlden, H. Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia. Ann. Neurol. 73: 546-553, 2013. [PubMed: 23424103] [Full Text: https://doi.org/10.1002/ana.23832]
Kancheva, D., Chamova, T., Guergueltcheva, V., Mitev, V., Azmanov, D. N., Kalaydjieva, L., Tournev, I., Jordanova, A. Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia. Mov. Disord. 30: 854-858, 2015. [PubMed: 25772097] [Full Text: https://doi.org/10.1002/mds.26196]
Leandro-Garcia, L. J., Leskela, S., Landa, I., Montero-Conde, C., Lopez-Jimenez, E., Leton, R., Cascon, A., Robledo, M., Rodriguez-Antona, C. Tumoral and tissue-specific expression of the major human beta-tubulin isotypes. Cytoskeleton 67: 214-223, 2010. [PubMed: 20191564] [Full Text: https://doi.org/10.1002/cm.20436]
Lee, M. G.-S., Loomis, C., Cowan, N. J. Sequence of an expressed human beta-tubulin gene containing ten Alu family members. Nucleic Acids Res. 12: 5823-5836, 1984. [PubMed: 6462917] [Full Text: https://doi.org/10.1093/nar/12.14.5823]
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.
Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., and 17 others. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann. Neurol. 73: 537-545, 2013. [PubMed: 23595291] [Full Text: https://doi.org/10.1002/ana.23829]
Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies. Neurology 82: 2230-2237, 2014. [PubMed: 24850488] [Full Text: https://doi.org/10.1212/WNL.0000000000000535]
Parker, N. Hereditary whispering dysphonia. J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985. [PubMed: 3156966] [Full Text: https://doi.org/10.1136/jnnp.48.3.218]
Purnell, S. M., Bleyl, S. B., Bonkowsky, J. L. Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy. Pediat. Neurol. 50: 608-611, 2014. [PubMed: 24742798] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2014.01.051]
Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N. Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum. Brain Dev. 31: 582-587, 2009. [PubMed: 18851904] [Full Text: https://doi.org/10.1016/j.braindev.2008.09.003]
Savage, C., Xue, Y., Mitani, S., Hall, D., Zakhary, R., Chalfie, M. Mutations in the Caenorhabditis elegans beta-tubulin gene mec-7: effects on microtubule assembly and stability and on tubulin autoregulation. J. Cell Sci. 107: 2165-2175, 1994. [PubMed: 7983175] [Full Text: https://doi.org/10.1242/jcs.107.8.2165]
Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others. A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. Am. J. Hum. Genet. 92: 767-773, 2013. [PubMed: 23582646] [Full Text: https://doi.org/10.1016/j.ajhg.2013.03.018]
Vemula, S. R., Xiao, J., Bastian, R. W., Momcilovic, D., Blitzer, A., LeDoux, M. S. Pathogenic variants in TUBB4A are not found in primary dystonia. Neurology 82: 1227-1230, 2014. [PubMed: 24598712] [Full Text: https://doi.org/10.1212/WNL.0000000000000294]
Wakusawa, K., Haginoya, K., Kitamura, T., Togashi, N., Ishitobi, M., Yokoyama, H., Higano, S., Onuma, A., Nara, T., Iinuma, K. Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum. Tohoku J. Exp. Med. 209: 163-167, 2006. [PubMed: 16707859] [Full Text: https://doi.org/10.1620/tjem.209.163]
Yen, T. J., Machlin, P. S., Cleveland, D. W. Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin. Nature 334: 580-585, 1988. [PubMed: 3405308] [Full Text: https://doi.org/10.1038/334580a0]