SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis

• DOI: 10.1172/jci.insight.173484
• Publication Date: 2025-03-25T16:15:47Z
• Authors: Nina Bögershausen; Büsranur Cavdarli; Taylor H. Nagai; Miroslav P. Milev; Alexander Wolff; Mahsa Mehranfar; Julia Schmidt; Dharmendra Choudhary; Óscar Gutiérrez-G...; Lukas Cyganek; Djenann Saint-Dic; Arne Zibat; Karl Köhrer; Tassilo E. Wollen...; Dagmar Wieczorek; Janine Altmüller; Tatiana Borodina; Dilek Kaçar; Göknur Haliloğlu; Yun Li; Christian Thiel; Michael Sacher; Ela W. Knapik; Gökhan Yigit; Bernd Wollnik
• Keywords: Technology Platforms; Genes, Cells and Cell-Based Medicine [Topic 1]

As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The four SEC24 proteins (A-D) are essential COPII components involved in cargo selection packaging. A human disorder corresponding to alterations currently only known SEC24D. Here, we report that biallelic loss SEC24C leads syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, cataracts an extended consanguineous family with affected individuals. We show knockout sec24C zebrafish recapitulates important aspects phenotype. SEC24C-deficient fibroblasts display expression several as well impaired anterograde trafficking Golgi, indicating severe impact on function. Transcriptome analysis revealed deficiency also impacts proteasome autophagy pathways. Moreover, shift N-glycosylation pattern deregulation pathway suggest possible secondary alteration glycosylation, linking described congenital disorders glycosylation.