TTC14 dysfunction contributing to microcephaly and lissencephaly spectrum features through protein mislocalization...

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Congenital microcephaly and lissencephaly spectrum disorders involve impaired neuronal development.
• Genetic variants are often the underlying cause of these complex neurodevelopmental conditions.

Purpose of the Study:

• To identify and characterize a novel gene, Tetratricopeptide Repeat Domain 14 (TTC14), and its associated variant in a patient with microcephaly and developmental delay.
• To investigate the functional consequences of the TTC14 p.His30Arg variant on protein structure, localization, and cellular processes.

Main Methods:

• Trio-based whole exome sequencing to identify genetic variants.
• Structural modeling, molecular dynamics simulations, and interaction network analysis to assess protein stability and function.
• Analysis of mRNA and protein levels, protein localization, cell death, and cell cycle progression in patient-derived fibroblasts.
• Gene ontology analysis to determine the role of TTC14 in cellular pathways.

Main Results:

• A novel homozygous missense variant (c.89 A>G; p.His30Arg) in TTC14 was identified in a patient with microcephaly, epileptic spasms, and global developmental delay.
• The p.His30Arg substitution destabilized the TTC14 protein, altered its localization from the nucleus to the cytosol, and led to aggregate formation.
• Proband fibroblasts showed increased cell death and altered cell cycle progression.
• TTC14 interacts with RNA processing proteins, suggesting a role in RNA metabolism during neurodevelopment.

Conclusions:

• The TTC14 gene plays a critical role in neurodevelopment, particularly in RNA metabolism.
• The identified p.His30Arg variant impairs TTC14 function, likely contributing to a neurodevelopmental disorder within the lissencephaly spectrum.
• TTC14 is a potential candidate gene for cortical malformation syndromes.