TBCD, or tubulin-folding co-factor D, is one of five tubulin-specific chaperones. It plays a pivotal role in the assembly and disassembly of α/β-tubulin heterodimers, thus being crucial for microtubule dynamics, which is essential for various cellular processes including centriologenesis, spindle organization, and cell abscission [1]. It is also involved in the proper folding and assembly of tubulin subunits, a function important for normal cell function throughout the body, especially in neurons [1,3].

Mutations in TBCD have been associated with a range of neurodegenerative and neurodevelopmental disorders. In humans, biallelic TBCD mutations in affected individuals from multiple families led to early-onset progressive neurodegenerative encephalopathy, characterized by features such as early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, growth retardation, muscle weakness/atrophy, and respiratory failure [3]. In vitro cell experiments showed impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin, and in vivo experiments using Drosophila melanogaster olfactory projection neurons indicated loss of function due to TBCD mutations [3]. Other phenotypes associated with TBCD mutations include distal motorneuronopathy, mild mental retardation with corpus callosum hypoplasia [2], and early-onset neurodegeneration with failure to thrive, hypotonia, muscle weakness, atrophy, and seizures [4].

In conclusion, TBCD is essential for microtubule dynamics and normal cellular function, especially in neurons. Research on TBCD-related mutations in humans has revealed its significance in neurodegenerative and neurodevelopmental diseases. Understanding the role of TBCD through such studies may provide insights into the mechanisms of these diseases and potentially lead to new treatment strategies.

References:

1. Fanarraga, Mónica López, Bellido, Javier, Jaén, Cristina, Villegas, Juan Carlos, Zabala, Juan Carlos. 2010. TBCD links centriologenesis, spindle microtubule dynamics, and midbody abscission in human cells. In PloS one, 5, e8846. doi:10.1371/journal.pone.0008846. https://pubmed.ncbi.nlm.nih.gov/20107510/

2. Caputo, Maria, Martinelli, Ilaria, Fini, Nicola, Mandrioli, Jessica, Zucchi, Elisabetta. 2023. A Variant in TBCD Associated with Motoneuronopathy and Corpus Callosum Hypoplasia: A Case Report. In International journal of molecular sciences, 24, . doi:10.3390/ijms241512386. https://pubmed.ncbi.nlm.nih.gov/37569761/

3. Miyake, Noriko, Fukai, Ryoko, Ohba, Chihiro, Saitsu, Hirotomo, Matsumoto, Naomichi. 2016. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. In American journal of human genetics, 99, 950-961. doi:10.1016/j.ajhg.2016.08.005. https://pubmed.ncbi.nlm.nih.gov/27666374/

4. Chen, Chih-Ling, Lee, Chien-Nan, Chien, Yin-Hsiu, Chang, Tung-Ming, Lee, Ni-Chung. 2021. Novel Compound Heterozygous Variants in TBCD Gene Associated with Infantile Neurodegenerative Encephalopathy. In Children (Basel, Switzerland), 8, . doi:10.3390/children8121140. https://pubmed.ncbi.nlm.nih.gov/34943336/