Germline C1GALT1C1 mutation causes a multisystem chaperonopathy
Proceedings of the National Academy of Sciences, vol. 120, pp. e2211087120
Abstract
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, causing 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 transmembrane 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 (GalNAcα1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient transfection 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.
Authors 26
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany
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Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany
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Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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Affiliation as printed
Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
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Beth Israel Deaconess Medical Center · Harvard University · Guangdong Academy of Medical Sciences · Guangdong Provincial People's Hospital · Southern Medical University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, China
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Affiliation as printed
Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
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Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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University of Bern · Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany
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University of Cologne · University Hospital Cologne
Affiliation as printed
Children’s and Adolescents’ Hospital, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany
Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany
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Affiliation as printed
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
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Affiliation as printed
Centre de Biotechnologie Cellulaire and CBC BioTec Biobank, Centre de Ressources Biologiques, Hospices Civils de Lyon, 69229 Lyon, France
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University Hospital Heidelberg
Affiliation as printed
Institute of Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany
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Universitätsklinik Marien Hospital Herne · Ruhr University Bochum
Affiliation as printed
Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, 44625 Herne, Germany
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Affiliation as printed
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany
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Martin Häusler Aachen Division of Neuropediatrics and Social Pediatrics Department of Pediatrics, Medical Faculty
Affiliation as printed
Division of Neuropediatrics and Social Pediatrics, Department of Pediatrics, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
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University of Cologne · University Hospital Cologne
Affiliation as printed
Children’s and Adolescents’ Hospital, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Department of Nephropathology, Institute of Pathology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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Affiliation as printed
Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
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Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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University of Cologne · Max Delbrück Center · Berlin Institute of Health at Charité - Universitätsmedizin Berlin
Affiliation as printed
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Genomics, 10178 Berlin, Germany
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
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University of Cologne · University Hospital Cologne
Affiliation as printed
Children’s and Adolescents’ Hospital, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany
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Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany
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