Germline C1GALT1C1 mutation causes a multisystem chaperonopathy

作者:Erger, Florian; Aryal, Rajindra P.; Reusch, Bjoern; Matsumoto, Yasuyuki; Meyer, Robert; Zeng, Junwei; Knopp, Cordula; Noel, Maxence; Muerner, Lukas; Wenzel, Andrea; Kohl, Stefan; Tschernoster, Nikolai; Rappl, Gunter; Rouvet, Isabelle; Schroeder-Braunstein, Jutta; Seibert, Felix S.; Thiele, Holger; Haeusler, Martin G.; Weber, Lutz T.; Buettner-Herold, Maike; Elbracht, Miriam; Cummings, Sandra F.; Altmueller, Janine; Habbig, Sandra; Cummings, Richard D.*; Beck, Bodo B.*
来源:PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2023, 120(22).
DOI:10.1073/pnas.2211087120

摘要

Mutations in genes encoding molecular chaperones can lead to chaperonopathies, but none have so far been identified causing congenital disorders of glycosylation. Here we identified two maternal half-brothers with a novel chaperonopathy, caus-ing impaired protein O-glycosylation. The patients have a decreased activity of T-synthase (C1GALT1), an enzyme that exclusively synthesizes the T-antigen, a ubiquitous O-glycan core structure and precursor for all extended O-glycans. The T-synthase function is dependent on its specific molecular chaperone Cosmc, which is encoded by X-chromosomal C1GALT1C1. Both patients carry the hemizygous variant c.59C>A (p.Ala20Asp; A20D-Cosmc) in C1GALT1C1. They exhibit developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome. 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 occurs within the trans -membrane domain of Cosmc, resulting in dramatically reduced expression of the Cosmc protein. Although A20D-Cosmc is functional, its decreased expression, though in a cell or tissue-specific manner, causes a large reduction of T-synthase protein and activity, which accordingly leads to expression of varied amounts of pathological Tn-antigen (GalNAc & alpha;1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient trans-fection of patient lymphoblastoid cells with wild-type C1GALT1C1 partially rescued the T-synthase and glycosylation defect. Interestingly, all four affected individuals have high levels of galactose-deficient IgA1 in sera. These results demonstrate that the A20D-Cosmc mutation defines a novel O-glycan chaperonopathy and causes the altered O-glycosylation status in these patients.

  • 单位
    南方医科大学; 1; 广东省人民医院