Alternative titles; symbols
HGNC Approved Gene Symbol: TUBB
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:30,720,352-30,725,422 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Cortical dysplasia, complex, with other brain malformations 6 | 615771 | Autosomal dominant | 3 |
| Symmetric circumferential skin creases, congenital, 1 | 156610 | Autosomal dominant | 3 |
Cowan et al. (1981) identified presumed tubulin pseudogenes, and Wilde et al. (1982) presented evidence that one such gene was derived from its corresponding mRNA. Wilde et al. (1982) described the structure of 2 pseudogenes. One had no introns but had a polyadenylate signal and an oligoadenylate trait at its 3-prime end. It may have originated by reverse transcription of a processed messenger RNA followed by reintegration of the complementary DNA copy into the genome. Cleveland and Sullivan (1985) stated that in the human and rat genomes a few authentic tubulin genes are present 'amid a sea of pseudogenes.' Many of these are 'retroposons': they lack all intervening sequences, have a long coded poly(A) tract at the 3-prime end, and have a 10- to 15-basepair direct repeat in the 5-prime and 3-prime flanking DNA. Isolation of cDNA clones indicate the existence of 2 functional alpha-tubulin genes and 3 functional beta-tubulin genes in man. There may be more.
Crabtree et al. (2001) cloned beta-tubulin, which they designated beta-Ib tubulin, from a human retina cDNA library.
Using database analysis, Leandro-Garcia et al. (2010) identified 8 major beta-tubulins, including TUBB. Quantitative RT-PCR showed variable TUBB expression in all 21 normal human tissues examined, with highest expression in thymus, followed by brain, heart, and ovary, and lowest expression in testis and prostate. TUBB was the major tubulin-beta isotype in ovary, lymph node, thymus, and fetal liver. Abnormal TUBB expressed was detected in several tumor tissues compared with their normal counterparts.
Using quantitative real-time PCR, Breuss et al. (2012) found that TUBB5 was among a group of beta-tubulins highly expressed in human fetal brain. TUBB5 was more highly expressed at gestational week 13 than at gestational week 22. In mouse embryonic brain, Tubb5 was more highly expressed than other beta-tubulins at all time points examined, with highest expression at embryonic day 14.5 (E14.5). In situ hybridization detected high Tubb5 expression throughout developing cortex, with strong expression in the preplate at E12.5 and in the subventricular zone at E14.5. Use of a fluorescence-tagged reporter indicated that Tubb5 protein was expressed in radial glial cells, intermediate progenitors, migrating neurons, and postmitotic neurons.
By immunostaining in developing skin of 4-day-old mice, Isrie et al. (2015) demonstrated expression of Tubb in the proliferative layers of the epidermis and the developing hair follicle.
Microtubules are constituent parts of a diverse variety of eukaryotic cell structures, e.g., the mitotic apparatus, cilia, flagella, and elements of the cytoskeleton. They consist principally of 2 soluble proteins, alpha- and beta-tubulin, each with a molecular weight of about 55,000. They are transcribed from different genes. Using chicken alpha- and beta-tubulin cDNA, Cleveland et al. (1980) concluded that human DNA contains about 14 copies per genome of alpha- and beta-tubulin genes. There is much evidence for evolutionary conservation of the tubulins. See 602660 for additional background.
Based on Southern blot analysis with a chicken beta-tubulin probe, Lee et al. (1983) stated that beta-tubulin in humans is coded by a large gene family with 15 to 20 members. One subfamily, identified by using the 3-prime untranslated region of a beta-tubulin gene as a probe to screen genomic libraries, consists of an expressed gene, designated M40, and 3 processed pseudogenes. Two alternative polyadenylation sites cause the M40 gene to be expressed as 2 mRNAs, 1.8 and 2.6 kb. Two of the pseudogenes are derived from the shorter mRNA, and the third is derived from the 2.6 kb mRNA.
Crabtree et al. (2001) determined that the TUBB gene contains 4 exons.
With gene clones in somatic cell hybrids, Floyd-Smith et al. (1985) found that the M40 gene is situated on chromosome 6 in the segment 6pter-p21. Of the pseudogenes, 1 was found to be on chromosome 8 and 1 on chromosome 13. Volz et al. (1994) determined that the TUBB gene is located in the HLA class I region at 6p21.3 by study of a panel of deletion mutant cell lines and radiation-reduced hybrids containing fragments of chromosome 6. A long-range restriction map, generated by rotating field gel electrophoresis, showed that TUBB maps to a segment 170 to 370 kb telomeric of HLA-C (142840) and proximal to HLA-E (143010).
Crystal Structure
Ravelli et al. (2004) determined the crystal structure, at 3.5-angstrom resolution, of tubulin in complex with colchicine and with the stathmin-like domain of RB3 (RB3-SLD). It shows the interaction of 2 tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments showed changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlated with the loss of lateral contacts and provided a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, Ravelli et al. (2004) concluded that the structure of the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity; they demonstrated that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.
Wang and Nogales (2005) presented 2 structures corresponding to the start and end points in the microtubule polymerization and hydrolysis cycles that illustrated the consequences of nucleotide state on longitudinal and lateral assembly. In the absence of depolymerizers, GDP-bound tubulin showed distinctive intra-dimer and inter-dimer interactions and thus distinguished the GTP and GDP interfaces. A cold-stable tubulin polymer with the nonhydrolyzable GTP analog GMPCPP, containing semiconserved lateral interactions, supported a model in which the straightening of longitudinal interfaces happens sequentially, starting with a conformational change after GTP binding that straightens the dimer enough for the formation of lateral contacts into a nontubular intermediate. Closure into a microtubule does not require GTP hydrolysis.
Yen et al. (1988) described a mechanism of autoregulation of the stability of tubulin mRNA by the intracellular concentration of tubulin heterodimers. Transfection experiments using gene constructs prepared by site-directed mutagenesis demonstrated that the recognition element for autoregulated RNA instability is the amino-terminal tetrapeptide encoded by the gene.
Smith et al. (2009) showed that mutant huntingtin (613004), disrupted intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. Mutant huntingtin impaired glucose-stimulated insulin secretion in insulin-producing beta cells, without altering stored levels of insulin. Mutant huntingtin also retarded post-Golgi transport, and the speed of insulin vesicle trafficking was reduced. There was an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Smith et al. (2009) proposed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.
By in utero electroporation of short hairpin RNA (shRNA) into progenitor cells of the ventricular zone in E14.5 mice, Breuss et al. (2012) found that knockdown of Tubb5 during development led to a long-term neuronal positioning defect. Depletion of Tubb5 disturbed the cell cycle of neurogenic progenitors and reduced the number of neurons at the cortical plate, concomitant with accumulation of cells within the ventricular zone and intermediate zone.
By in utero electroporation of Tubb5 shRNA or overexpression of wildtype TUBB5 or TUBB5 with pathogenic mutations into E14.5 mouse embryos, Ngo et al. (2014) found that Tubb5 had a role in morphology of cortical neurons, axonal outgrowth, and density and maturation of dendritic spines. Tubb5 also influenced the rate of microtubule growth.
Lin et al. (2020) identified human TTC5 (619014) as a cytosolic factor that specifically recognized and interacted with the N-terminal autoregulatory motifs of nascent alpha-tubulin (TUBA1B; 602530) and beta-tubulin (TUBB) early during their translation for tubulin autoregulation. Structural analysis of the tubulin-ribosome nascent chain (RNC) complex showed that TTC5 made 2 contacts with the ribosome near the ribosome exit tunnel, with its peptide-binding groove positioned to engage nascent tubulins shortly after they emerged from the ribosome. TTC5 knockout analysis in human cells confirmed that TTC5 engagement of nascent tubulin at the ribosome was required for tubulin mRNA degradation for tubulin autoregulation, as well as for accurate mitosis. The authors also found that cells contained an inhibitory factor that prevented TTC5 engagement of tubulin RNCs when the alpha- and beta-tubulin concentration was normal. This TTC5 inhibitor was inactivated when cells perceived excess alpha- and beta-tubulin, freeing TTC5 to engage tubulin RNCs and trigger tubulin mRNA degradation.
Complex Cortical Dysplasia with Other Brain Malformations 6
In 3 unrelated children with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771) and microcephaly, Breuss et al. (2012) identified 3 different de novo heterozygous missense mutations in the TUBB gene (191130.0001-191130.0003). The gene was chosen for study because of its role in mouse neuronal development. In vitro and in vivo functional studies showed that the mutations affected the assembly of tubulin heterodimers in different ways and disrupted cerebral neurogenic division and/or migration. The findings suggested a loss of function, although a dominant-negative effect could not be ruled out. Breuss et al. (2012) noted that patients with TUBB mutations share structural brain abnormalities in common with other tubulinopathies resulting from mutations in genes encoding other tubulins, including TUBA1A (602529), TUBB2B (612850), and TUBB3 (602661).
Congenital Symmetric Circumferential Skin Creases 1
In 3 unrelated children with congenital symmetric circumferential skin creases (CSCSC1; 156610), Isrie et al. (2015) identified de novo missense mutations in the TUBB gene: 2 patients were heterozygous for a Q15K substitution (191130.0004) and 1 was heterozygous for a Y222F substitution (191130.0005). Functional analysis indicated that both mutations compromise microtubule dynamics.
Nonsmall Cell Lung Cancer
Monzo et al. (1999) examined constitutional genomic DNA and paired tumor DNA from 43 Spanish and 6 American stage IIIb or IV nonsmall cell lung cancer patients who had been treated with paclitaxel. They identified mutations in the TUBB gene in 16 patients (33%; 95% CI, 20.7-45.3%); 1 mutation was in exon 1 and the remainder were in exon 4. None of the patients with TUBB mutations had an objective response to chemotherapy, whereas 13 of 33 (39.4%; 95% CI, 22.8-56%; p = 0.01) patients without mutations had complete or partial responses. Median survival was 3 months for the 16 patients with TUBB mutations and 10 months for the 33 patients without mutations (p = 0.0001). Monzo et al. (1999) concluded that TUBB gene mutations are a strong predictor of response to paclitaxel and that these mutations may represent a novel mechanism of resistance.
Using direct sequence analysis following RT-PCR, Tsurutani et al. (2002) examined exon 4 of the TUBB gene for mutations in 20 lung cancer cell lines and in 22 specimens from Japanese lung cancer patients. Three silent mutations were detected, 2 of which were found to be polymorphisms present in normal tissue. Tsurutani et al. (2002) concluded that TUBB gene mutations might not play a major role in the mechanism of resistance to paclitaxel in Japanese lung cancer patients.
Using exonic primers, de Castro et al. (2003) analyzed exon 4 of the TUBB gene in tumor specimens from 15 patients with stage IIIB and IV nonsmall cell lung cancer. They found gene sequence alterations in 13 patients (87%); however, all alterations disappeared when sequenced with intronic primers. De Castro et al. (2003) concluded that point mutations demonstrated with exonic but not intronic primers are probably due to beta-tubulin pseudogenes present in advanced nonsmall cell lung cancer specimens, and that this may account for discrepancies in published results.
Bianchi et al. (1992) presented evidence suggesting the involvement of an HLA-linked gene in the immotile cilia syndrome (ICS; 244400). They also had suggestive evidence of linkage between this form of ICS and the TUBB locus.
In a 2-year-old Caucasian boy with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation in the TUBB gene, resulting in a met299-to-val (M299V) substitution at a highly conserved residue in a loop following helix 9. In vitro functional expression assays showed that the M299V mutation decreased the ability of the protein to assemble into tubulin heterodimers. Overexpression of the mutant protein in the developing mouse brain increased the mitotic index of neurons and decreased the number of neurons in the cortical plate, similar to findings observed in Tubb-null mice. The findings were consistent with a neuronal migratory defect. The patient had severely delayed development, microcephaly (-2.5 SD), and retinal dysplasia. Brain MRI showed focal polymicrogyria, localized band heterotopia, dysmorphic basal ganglia, partial agenesis of the corpus callosum, and hypoplastic and dysplastic cerebellum.
In a 4-year-old Sri Lankan patient with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation in the TUBB gene, resulting in a val353-to-ile (V353I) substitution at a highly conserved residue on the intradimer interface. Overexpression of the mutant protein in the developing mouse brain increased the mitotic index of neurons and decreased the number of neurons in the cortical plate, similar to findings observed in Tubb-null mice. The findings were consistent with a neuronal migratory defect. The patient had severely delayed development and microcephaly (-4 SD). Brain imaging showed dysmorphic basal ganglia, white matter abnormalities, and thin, short corpus callosum. Cortical dysgenesis was not apparent. The patient had a family history of microcephaly without mental retardation, suggesting that another genetic factor contributed to that feature.
In a 2-year-old girl of Vietnamese and Caucasian descent with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation in the TUBB gene, resulting in a glu401-to-lys (E401K) substitution at a highly conserved residue on the surface of the intradimer interface. In vitro functional expression assays showed that the E401K mutation arrested the assembly pathway of alpha/beta-tubulin; the mutant protein was unable to coassemble into a tubulin heterodimer but was instead distributed throughout the cytoplasm. Overexpression of the mutant protein in the developing mouse brain resulted in a mild increase in the mitotic index of neurons and decreased the number of neurons in the cortical plate, similar to findings observed in Tubb-null mice. The findings were consistent with a neuronal migratory defect. The patient had mild developmental delay, microcephaly (-4 SD), dysmorphic basal ganglia, and partial agenesis of the corpus callosum. Cortical dysgenesis was not apparent.
In a Canadian boy and a Turkish girl with congenital symmetric circumferential skin creases (CSCSC1; 156610), originally reported by Leonard (2002) and Ulucan et al. (2013), respectively, Isrie et al. (2015) identified heterozygosity for a c.43C-A transversion (c.43C-A, NM_178014.3) in the TUBB gene, resulting in a gln15-to-lys (Q15K) substitution. In both probands the mutation arose de novo. Kinetic analysis of TUBB heterodimer assembly reactions demonstrated a profound reduction in formation of the TBCD/beta-tubulin intermediate complex and an even greater reduction in the yield of assembled heterodimers with the Q15K mutant compared to wildtype. Microtubule plus-end tracking experiments showed a significant increase in velocity with overexpression of wildtype TUBB compared to control, but this increase was not seen with the Q15K mutant. (In the article by Isrie et al. (2015), the amino acid substitution is cited as gln15-to-lys in some places and as glu15-to-lys in others.)
In a Norwegian boy with congenital symmetric circumferential skin creases (CSCSC1; 156610), Isrie et al. (2015) identified heterozygosity for a de novo c.665A-T transversion (c.665A-T, NM_178014.3) in the TUBB gene, resulting in a tyr222-to-phe (Y222F) substitution. Kinetic analysis of TUBB heterodimer assembly reactions demonstrated a marked reduction in the formation of the TBCA/beta-tubulin intermediate complex and in the yield of assembled heterodimers with the Y222F mutant compared to wildtype. Microtubule plus-end tracking experiments showed a significant decrease in velocity with overexpression of the Y222F mutant compared to wildtype, to less than control levels.
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