Germline C1GALT1C1 Mutation Causes a Multisystemic Chaperonopathy with Global Deficiency of Core 1-derived O-Glycosylation

Abstract The galactosyltransferase T-synthase exclusively synthesizes the T-antigen, a ubiquitous Oglycan core structure. Its function is dependent on its specific molecular chaperone, Cosmc (C1GALT1C1). In two maternal half-brothers with developmental delay, immunodeficiency, short stature, thrombocytopenia and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome, we identified the hemizygous variant c.59C > A (p.Ala20Asp) in Xchromosomal C1GALT1C1. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant within the transmembrane domain of Cosmc causes dramatically reduced expression of the Cosmc chaperone with a significant reduction of Tsynthase enzyme activity, resulting in incomplete O-glycosylation. Transfection of patient cells with wildtype C1GALT1C1 partially rescued this glycosylation defect. We also detected very high levels of galactose-deficient IgA1 in all four affected individuals.