Hudson Freeze, PhD
Director, Sanford Children's Health Research Center
Director and Professor, Human Genetics Program
Sanford Burnham Prebys Medical Discovery Institute (SBP)
La Jolla, CA USAShort CVAbstract
Inherited and de novo
variants in genes that affect the synthesis and assembly of glycoconjugates (glycans) cause Congenital Disorders of Glycosylation (CDG). Defects occur in all major glycan biosynthetic and homeostasis pathways. They cause a plethora of multisystemic pathologies depending on the glycan(s) affected. Currently, over 170 disorders fall under this broad umbrella. In the United States, the Frontiers of Congenital Disorders of Glycosylation Consortium enrolls and tracks over 200 patients to collect natural history, identify biomarkers, and conduct multiple clinical trials.
Our laboratory studies Saul Wilson Syndrome (SWS), a primordial dwarfism with progeroid features. A recurrent, dominant heterozygous mutation in COG4
causes SWS. The protein is a member of a soluble 8-subunit complex responsible for vesicle trafficking between the ER and Golgi. Using patient fibroblasts, HEK293 cells, and SWS-expressing chondrosarcoma cells, we found that the SWS mutation subtly alters glycosylation, and selectively disrupts protein secretion and extracellular matrix formation. Secretome, RNAseq and Bio-ID interactome analyses show highly selective alterations in SWS-COG4 chondrosarcoma cells vs. WT or COG4 KO cells.
Overall, we believe that SWS COG4 mutation alters the structure of COG4, changing its selective binding to both cytoplasmic trafficking proteins and interaction with a subset of trafficking vesicles that lead to the impaired, selective secretion of multiple matrix components. To compensate for these disruptions, cells selectively alter the transcription of other interacting factors. In support of this, a zebrafish model of SWS shows shortened body length and disrupted chondrogenesis due to accumulation of glypican, a compensatory induction of Wnt4, and altered Wnt signaling.