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

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 4 SEC24 proteins (A-D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently known only for SEC24D. Here, we reported that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with 4 affected individuals. We showed that knockout of sec24C in zebrafish recapitulated important aspects of the human phenotype. SEC24C-deficient fibroblasts displayed alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also affected the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggested a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.

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Publication Details

Journal
JCI Insight
Published
2025-03-25
DOI
https://doi.org/10.1172/jci.insight.173484
Citations
4
Primary Topic
Amino Acid Enzymes and Metabolism
Type
article
Field-Weighted Citation Impact
4.45

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article

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

Büşranur Çavdarlı, Alexander Wolff, Christian Thiel, Arne Zibat et al.
4 citations
JCI Insight
Amino Acid Enzymes and Metabolism
4.45
article

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

Büşranur Çavdarlı, Alexander Wolff, Christian Thiel, Arne Zibat, Tassilo Erik Wollenweber, Dilek Kaçar, Nina Bögershausen, Janine Altmüller, Yun Li, Michael Sacher, Mahsa Mehranfar, Djenann Saint‐Dic, Óscar Gutiérrez‐Gutiérrez, Lukas Cyganek, Dharmendra Choudhary, Karl Köhrer, Julia Schmidt, Dagmar Wieczorek, Göknur Haliloğlu, Tatiana Borodina, Miroslav P. Milev, Gökhan Yigit, Bernd Wollnik, Ela W. Knapik, Taylor Nagai
article en
4 citations

Abstract

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 4 SEC24 proteins (A-D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently known only for SEC24D. Here, we reported that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with 4 affected individuals. We showed that knockout of sec24C in zebrafish recapitulated important aspects of the human phenotype. SEC24C-deficient fibroblasts displayed alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also affected the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggested a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.

JCI InsightVol. 10(9)
Bilkent University (TR), Vanderbilt University (US), Max Delbrück Center (DE), Heidelberg University (DE), Düsseldorf University Hospital (DE), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), Universitätsmedizin Göttingen (DE), German Centre for Cardiovascular Research (DE), Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE), Genomics Medicine (Ireland) (IE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Ankara Yıldırım Beyazıt University (TR), Ankara Bilkent City Hospital (TR), Heinrich Heine University Düsseldorf (DE), McGill University (CA), Concordia University (CA), Hacettepe University (TR), Vanderbilt University Medical Center (US)
Deutsches Zentrum für Herz-Kreislaufforschung, Deutsche Forschungsgemeinschaft, National Institutes of Health
Gender equality
Openalex Percentile: Top 7%
Amino Acid Enzymes and Metabolism
4.45
DOIOpen Access PDFOpenAlex
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