Akademik Veri Yönetim Sistemi
JOURNAL OF HUMAN GENETICS, cilt.67, sa.5, ss.279-284, 2022 (SCI-Expanded)
Background The trafficking protein particle (TRAPP) complex subunit 9 (C9) protein is a member of TRAPP-II complexes and regulates vesicle trafficking. Biallelic mutations in the TRAPPC9 gene are responsible for intellectual disability with expanded developmental delay, epilepsy, microcephaly, and brain atrophy. TRAPPC9-related disease list is still expanding, however, the functional effects of only a limited fraction of these have been studied. Methods In a patient with a pathological variant in TRAPPC9, clinical examination and cranial imaging findings were evaluated. Whole-exome sequencing, followed by Sanger sequencing was performed to detect and verify the variant. To confirm the functional effect of the mutation; variant mRNA and protein expression levels were evaluated by qRT-PCR and Western blotting. Immunostaining for TRAPPC9 and lipid droplet accumulation were examined. Results We have identified a novel homozygous c.696C>G (p.Phe232Leu) pathogenic variant in TRAPPC9 (NM_031466.6) gene as a cause of severe developmental delay. Functional characterization of the TRAPPC9 variant resulted in decreased mRNA and protein expression. The intracellular findings showed that TRAPPC9 protein build-up around the nucleus in mutant type while there was no specific accumulation in the control cell line. This disrupted protein pattern affected the amount of neutral lipid-carrying vesicles and their homogenous distribution at a decreasing level. Conclusion Biallelic variants in the TRAPPC9 gene have been reported as the underlying cause of intellectual disability. This study provides functional evidence of the novel variant in TRAPPC9 We demonstrated that the loss of function variant exclusively targeting TRAPPC9 may explicate the neurological findings through vesicle trafficking.