Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway
We present a detailed description of the neuropathology and MR imaging characteristics - adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.
Study identified a homozygous novel pathogenic missense mutation (c.1423G > A;p.Ala475Thr) in TBCD gene to be associated with concurrent hypofibrinogenemia and cortical atrophy.
TBCD protein was localized in the middle region and in the tail of the sperm while in the oocyte the localization was cytosolic.
Authors conclude that TBCD is a novel functional contributor to the mammalian cerebral cortex development, and that the pathological mechanism resulting from the mutations we describe is likely to involve compromised interactions with one or more TBCD-interacting effectors that influence the dynamics and behaviour of the neuronal cytoskeleton.
TBCD*ARL2*beta-tubulin complex represents a functional intermediate in the beta-tubulin folding pathway whose activity is regulated by the cycling of nucleotides on ARL2
Results identified ARL2 and TBCD, as important in tubulin folding and microtubule dynamics. Both ARL2 and TBCD also localize to centrosomes. [review]
We identified two candidate homozygous missense variants, R942Q in the TBCD gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp.
Intractable epilepsy, intellectual disability and acquired microcephaly, and cortical atrophy and thinned corpus callosum as major MRI features, caused by biallelic variants in TBCD.
Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of a neurodegenerative encephalopathy.
Findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain.
