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Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy
Noriko Miyake1, Ryoko Fukai2, Chihiro Ohba2
1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
American Journal of Human Genetics
|September 27, 2016
Summary
Biallelic mutations in the TBCD gene cause a severe neurodegenerative encephalopathy with early-onset brain atrophy and developmental regression. These TBCD mutations impair microtubule assembly, leading to loss of function and varied clinical severity.
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- Tubulin folding cofactor D (TBCD) is crucial for microtubule assembly.
- Microtubule defects are implicated in various neurodegenerative diseases.
Purpose of the Study:
- To identify the genetic cause of a unique neurodegenerative encephalopathy.
- To investigate the functional consequences of identified mutations.
Main Methods:
- Whole-exome sequencing was performed on affected individuals from four families.
- In vitro cell experiments assessed protein binding and function.
- In vivo Drosophila melanogaster models were used to study mutation effects.
Main Results:
- Biallelic TBCD mutations were identified in eight affected individuals.
- Mutant TBCD proteins showed impaired binding to key partners.
- TBCD mutations led to loss of function and neurodegenerative findings in vivo.
- Clinical severity correlated with residual mutant TBCD function.
Conclusions:
- TBCD mutations are responsible for a novel neurodegenerative encephalopathy.
- Impaired microtubule formation underlies the disease's pathomechanism.
- Further research into TBCD's role in neurodevelopment is warranted.
