TBCA - Tubulin-specific chaperone A - Homo sapiens (Human) - TBCA gene & protein
Missense mutation in the tubulin-specific chaperone E (Tbce) gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron. Complete information for TBCEL gene (Protein Coding), Tubulin Folding Cofactor E Tubulin-Specific Chaperone E-Like; LRRC35; Tubulin-Specific Chaperone .. from publication | Request up-to-date GeneHancer data (full dataset). Complete information for TBCE gene (Protein Coding), Tubulin Folding Cofactor E, And Dysmorphism; Tubulin-Specific Chaperone E; Tubulin-Folding Cofactor E .. from publication | Request up-to-date GeneHancer data (full dataset).
Both traits were mapped to 1qq44 and, despite the differences in clinical phenotype, were found to share an ancestral haplotype, suggesting a common founder mutation Diaz et al. The vast majority of patients carried a recurrent bp deletion Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center MTOC and perturbed microtubule polarity in diseased cells.
Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments.Top 5 Worst Dates
Thus, HRD and KCS1 are chaperone diseases caused by genetic defect in the tubulin assembly pathway, and these findings established a potential connection between tubulin physiology and the development of the parathyroid. The mutation in 2 families was found by whole-exome sequencing and confirmed by Sanger sequencing; the mutation in a pair of affected monozygotic twins in the third family was found by mutation scan of the TBCE gene.
Tubulin-specific chaperone E
Another patient patient with the disorder was found to be compound heterozygous for the IN mutation and a frameshift mutation The mutations segregated with the disorder in all families, and haplotype analysis of the families indicated a founder effect for IN.
Western blot analysis of patient fibroblasts showed significantly reduced amounts of mutant TBCE protein compared to controls, with lower levels in the patient with compound heterozygous mutations. RNA analysis of patient cells showed normal levels in the patient homozygous for IN, but decreased amounts of RNA in the compound heterozygous patient, suggesting that the 1-bp deletion resulted in nonsense-mediated mRNA decay.
Patient cells showed decreased levels of polymerized alpha-tubulin see and altered microtubule dynamics with decreased nucleation and markedly delayed microtubule repolymerization; microtubules were less abundant and strongly disorganized in both early and late stages of repolymerization, and there was loss of compaction in the Golgi apparatus.
There was also abnormal mitotic morphology with abnormal mitotic spindles and disorganized microtubule arrangement. The mutation is fully penetrant and expressivity does not depend on the genetic background. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization.
Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. The observations indicated that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggested that altered function of tubulin cofactors might be implicated in human motor neuron diseases.
Homozygous pmn mice have a severe motor neuron disease characterized by motor axon dying back and progressive loss of motor units. In pmn mice, Schaefer et al. Given the dramatic MT alterations on both pre- and postsynaptic sides, the NMJ phenotypes appear subtle.
The seemingly conflicting result that both overexpression and knockdown of tbce on the postsynaptic side led to similar phenotypes in synapse development supports an existing hypothesis that abnormal synaptic growth results from the disruption of MT dynamics, rather than from an alteration in the absolute quantity of MTs Jin, Increased neurotransmission, reflected in both EJP and mEJP amplitude, was observed upon presynaptic alteration of tbce expression, whereas postsynaptic manipulations of tbce showed normal neurotransmission.
This suggests that synaptic neurotransmission is sensitive to pre-but not postsynaptic MT alteration, although postsynaptic alterations of tbce had a significant effect on synapse development. Interestingly, both overexpression and knockdown of tbce on the presynaptic side led to a similar increase in both EJP and mEJP amplitude. The increase in mEJP amplitude could be caused by an increase in presynaptic vesicle size, an increase in the concentration of vesicular glutamate, or an increase in postsynaptic glutamate receptor sensitivity.
Autosomal dominant hereditary spastic paraplegia AD-HSP is a heterogeneous group of neurodegenerative disorders characterized by progressive and bilateral spasticity of the lower limbs, with specific degeneration of the longest axons in the CNS. However, the MT-related pathology of human patients with spastin mutation has not been documented Jin, Overexpression of spastin in Drosophila neuromusculature and in cultured cells causes dramatically fragmented and reduced MTs.
Surprisingly, morphologically normal muscles are present in patients with spastin mutations, although large-scale disruption of MT pathways was detected at the molecular level. No MT defects were reported in a mouse model in which the endogenous spastin is truncated.
Similarly, spastin-null mutants of Drosophila show no dramatic change in MT appearance in muscles, suggesting that Spastin plays a fine-tuning role in MT dynamics. Indeed, spastin nulls are late pupal lethal with a few adult escapers, further confirming a subtle role for Spastin in MT regulation.
By comparison, tbce nulls are embryonic lethal, whereas knockdown of tbce leads to a dramatically reduced MT network in Drosophila neuromusculature. This work shows that tbce is essential for early neuromuscular development in Drosophila. Overexpression of tbce produced increased MTs. This is the first report of increased MT formation when a tubulin chaperone is overexpressed, and is contrary to reports in other systems.
These in vivo data are consistent with the early in vitro observation that TBCD or TBCE in excess destroys tubulin heterodimers by sequestering the bound tubulin subunit, leading to the destabilization of the freed partner subunit Tian, The discrepancy between the overexpression result and findings of others could have several explanations: Further analyses are needed to reconcile the conflicts in the effects of TBCE overexpression in these different systems.
In general, however, tbce mutant phenotypes are consistent in all species examined so far, from yeast to human, indicating that the function of TBCE in promoting MT formation has been well-conserved throughout evolution Jin, Identification of a novel tubulin-destabilizing protein related to the chaperone cofactor E.
TBCA - Wikipedia
ADP ribosylation factor-like protein 2 Arl2 regulates the interaction of tubulin-folding cofactor D with native tubulin. Missense mutation in the tubulin-specific chaperone E Tbce gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron disease. Sto1p, a fission yeast protein similar to tubulin folding cofactor E, plays an essential role in mitotic microtubule assembly. Domain analysis of the tubulin cofactor system: Drosophila Tubulin-specific chaperone E functions at neuromuscular synapses and is required for microtubule network formation.
Possible regulation of microtubules through destabilization of tubulin.
Tubulin-specific chaperone A
The alpha- and beta-tubulin folding pathways. A missense mutation in Tbce causes progressive motor neuronopathy in mice. Structural insights into microtubule function. Functional dissection and hierarchy of tubulin-folding cofactor homologues in fission yeast.