hGGCX structural model characteristics
In order to understand the specific structural implication of the reported pathogenic variants a threading based GGCX in silicomodel was generated. In the simulation-equilibrated model, the majority of the C-terminal region from 420-758aa localized towards the ER luminal side including the propeptide binding site (495-513aa) (Parker et al., 2014) (Figure S3). Our model has multiple transmembrane domains with a distribution of both proper helices (116-134, 240-262, 274-292, 362-377aa) and molten globule regions (95-115, 394-419aa) resembling loosely packed helical structure, which also bears the glutamate binding site (393-404aa) (Figure S3) (Mutucumarana et al., 2000; Mutucumarana, Acher, Straight, Jin, & Stafford, 2003). In the absence of adequate structural templates and considering the large size of GGCX, our in silico model, albeit entirely hypothetical reflects the best possible structural representation of GGCX protein that can be achieved presently. ReportedGGCX variants are heterogeneously distributed throughout thisin silico model (Figure S4).