Impact of a Missense Mutation in TRAPPC12 in Patients with Progressive Encephalopathy, Brain Atrophy and Spasticity Phenotype without Microcephaly and Epilepsy

Objective: Various symptoms, including microcephaly, corpus callosum agenesis, cerebellar atrophy, spasticity, and epilepsy, are associated with variations in the TRAPPC12 gene. This diversity of features contributes to a broad range of mortality and morbidity. Identifying variations with functional conse quences is crucial for accurate diagnosis and appropriate counseling for affected families. This study presented the results of a functional analysis of a previously detected mutation.Materials and Methods: Patient-derived fibroblast cells (have a c.679T>G; p. Phe227Val variation) and the CCD1079Sk cell line (as a healthy control) were used. The relative protein expression of TRAPPC12 along with morphological changes, including Golgi integrity, endoplasmic reticulum (ER) structure, and vesicle distribution for neutral lipids, were assessed using immunofluorescent staining.Results: Protein expression analysis revealed an absence of the mature TRAPPC12 protein and the uncharacterized protein fragment (CGI-87) via mutation compared with the wild-type. Additionally, milder outcomes were observed for Golgi integrity, slight ER structure enlargement, and further vesicle distrib ution changes, particularly with the truncated TRAPPC12 protein.Conclusion: Despite the variant leading to a milder clinical phenotype without microcephaly and epilepsy, as previously reported, the study showed unstable protein expression and mild effects on Golgi and ER structures along with alterations in vesicle distribution throughout the cytoplasm. Despite the lack of mature TRAPPC12 protein expression and mild organelle impairments, the vesicle trafficking persisted. We showed that a single amino acid substitution might cause a loss of mature protein expression and also cause a milder disruption of organelles. More functional analyses are necessary to confirm these outcomes.