This report describes encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum (PEBAT), a progressive neurodegenerative encephalopathy; PEBAT exhibits autosomal recessive inheritance. The human gene implicated in this disease encodes tubulin folding cofactor D (TBCD), one of four cofactors required for folding of beta-tubulin; TBCD may be involved in the regulation of microtubule polymerization or depolymerization. There is a single orthologous gene in Drosophila, also designated TBCD, for which loss-of-function insertion alleles and RNAi-targeting constructs have been generated.
Multiple UAS constructs of the human Hsap\TBCD gene have been introduced into flies, including wild-type and variants associated with PEBAT. Partial heterologous rescue (functional complementation) is observed: axonal and dendritic morphological defects observed in TBCD1 neuronal clones can be partially rescued by expression of the wild-type human gene.
Variant(s) implicated in human disease tested (as transgenic human gene, TBCD): the M387R, R772C, and Y760* variant forms of the human gene have been introduced into flies. Function of the variants relative to wild-type was assessed using a functional complementation assay.
In the antennal lobe of the fly brain, single-cell clones of olfactory projection neurons have been used to assess neuron morphology in animals carrying a Dmel\TBCD loss-of-function mutation; neurons homozygous for the TBCD1 mutation display disruption of microtubules, resulting in ectopic arborization of dendrites and axon degeneration. Overexpression of Dmel\TBCD also results in microtubule disruption and ectopic dendrite arborization, suggesting that an optimum level of TBCD is required for neuronal morphogenesis. Physical and genetic interactions of Dmel\TBCD have been described; see below and in the TBCD gene report.
[updated Dec. 2017 by FlyBase; FBrf0222196]
[ENCEPHALOPATHY, PROGRESSIVE, EARLY-ONSET, WITH BRAIN ATROPHY AND THIN CORPUS CALLOSUM; PEBAT](https://omim.org/entry/617193)
[TUBULIN FOLDING COFACTOR D; TBCD](https://omim.org/entry/604649)
Optic atrophy is present in many patients and may be present early, since lack of visual tracking or eye contact may be noted at birth (http://disorders.eyes.arizona.edu/disorders/encephalopathy-early-onset-brain-atrophy-and-thin-corpus-callosum).
PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity (summary by Miyake et al., 2016, pubmed:27666374; Flex et al., 2016, pubmed:27666370). [from MIM:617193; 2017.12.04]
PEBAT is caused by homozygous or compound heterozygous mutation in the TBCD (tubulin-specific chaperone D) gene. [from MIM:617193; 2017.12.04]
Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination (summary by Miyake et al., 2016, pubmed:27666374; Flex et al., 2016, pubmed:27666370). [from MIM:617193; 2017.12.04]
TBCD encodes a tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly; it is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Involved in the regulation of microtubule polymerization or depolymerization, it modulates microtubule dynamics by capturing GTP-bound beta-tubulin. [from Gene Cards, TBCD; 2017.12.04]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human TBCD (1 Drosophila to 1 human); Dmel\TBCD shares 40% identity and 59% similarity with the human gene.
