Functional Characterization of a missense mutation in the TRAPPC12 gene presenting with progressive encephalopathy with brain atrophy and spasticity phenotype without microcephaly and epilepsy

Abstract

Abstract Background Variations in the TRAPPC12present many symptoms, including microcephaly, agenesis of corpus callosum, cerebellar atrophy, and epilepsy. These features indicate a broad range of mortality and morbidity. Identifying a variation with functional consequences provides an accurate diagnosis and proper counseling for the family. Herein, we describe the functional analysis of the homozygous missense variation NM_016030.6:c.679T>G in the TRAPPC12. Methods CCD1079Sk cell line (as a healthy control) and patient-derived fibroblast cells were evaluated for Golgi integrity, ER structure, and vesicle distribution and protein levels by Western blot. Results Protein expression showed an absence in the TRAPPC12 protein and an uncharacterized protein fragment (CGI-87). The lack of Golgi integrity and enlargement of ER structure were shown, and the vesicle distribution was even more disrupted via truncated TRAPPC12 protein. The effect of the variant resulted in milder clinical phenotype with the absence of microcephaly and epilepsy, which we had previously reported. Conclusion We have shown that the protein expression was disrupted, Golgi and ER structure negatively affected, resulting in a decreased and scattered number of vesicles while also having alterations in vesicle distribution. Nevertheless, these impairments did not arrest vesicle trafficking due to protein loss. However, unlike previous reports, we did not show a vesicle accumulation.