{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:32:23Z","timestamp":1790821943892,"version":"4.1.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"22","license":[{"start":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:00:00Z","timestamp":1684713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BE6072\/3-1"],"award-info":[{"award-number":["BE6072\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005615","name":"Beth Israel Deaconess Medical Center","doi-asserted-by":"publisher","award":["Glycoscience Fund"],"award-info":[{"award-number":["Glycoscience Fund"]}],"id":[{"id":"10.13039\/100005615","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BE6072\/2-1"],"award-info":[{"award-number":["BE6072\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["AL901\/2-1"],"award-info":[{"award-number":["AL901\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["AL901\/3-1"],"award-info":[{"award-number":["AL901\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,30]]},"abstract":"<jats:p>\n                    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 (\n                    <jats:italic>C1GALT1<\/jats:italic>\n                    ), 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\n                    <jats:italic>C1GALT1C1<\/jats:italic>\n                    . Both patients carry the hemizygous variant c.59C&gt;A (p.Ala20Asp; A20D-Cosmc) in\n                    <jats:italic>C1GALT1C1<\/jats:italic>\n                    . 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 (GalNAc\u03b11-O-Ser\/Thr\/Tyr) on multiple glycoproteins. Transient transfection of patient lymphoblastoid cells with wild-type\n                    <jats:italic>C1GALT1C1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2211087120","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T15:02:10Z","timestamp":1684767730000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Germline\n                    <i>C1GALT1C1<\/i>\n                    mutation causes a multisystem chaperonopathy"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2768-1702","authenticated-orcid":false,"given":"Florian","family":"Erger","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajindra P.","family":"Aryal","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Reusch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2606-2616","authenticated-orcid":false,"given":"Yasuyuki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Meyer","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Zeng","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"},{"name":"Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordula","family":"Knopp","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxence","family":"Noel","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Muerner","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"},{"name":"Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kohl","sequence":"additional","affiliation":[{"name":"Children\u2019s and Adolescents\u2019 Hospital, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai","family":"Tschernoster","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunter","family":"Rappl","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Rouvet","sequence":"additional","affiliation":[{"name":"Centre de Biotechnologie Cellulaire and CBC BioTec Biobank, Centre de Ressources Biologiques, Hospices Civils de Lyon, 69229 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Schr\u00f6der-Braunstein","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix S.","family":"Seibert","sequence":"additional","affiliation":[{"name":"Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, 44625 Herne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin G.","family":"H\u00e4usler","sequence":"additional","affiliation":[{"name":"Division of Neuropediatrics and Social Pediatrics, Department of Pediatrics, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4116-598X","authenticated-orcid":false,"given":"Lutz T.","family":"Weber","sequence":"additional","affiliation":[{"name":"Children\u2019s and Adolescents\u2019 Hospital, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"B\u00fcttner-Herold","sequence":"additional","affiliation":[{"name":"Department of Nephropathology, Institute of Pathology, Friedrich-Alexander Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Elbracht","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics and Genomic Medicine, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra F.","family":"Cummings","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Core Facility Genomics, 10178 Berlin, Germany"},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Habbig","sequence":"additional","affiliation":[{"name":"Children\u2019s and Adolescents\u2019 Hospital, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8918-5034","authenticated-orcid":false,"given":"Richard D.","family":"Cummings","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0495-7670","authenticated-orcid":false,"given":"Bodo B.","family":"Beck","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.787260"},{"key":"e_1_3_4_2_2","volume-title":"in Essentials of Glycobiology","author":"Varki A.","year":"2022","unstructured":"A. Varki , in Essentials of Glycobiology (Cold Spring Harbor NY, 2022)."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy032"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05770-9"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19020580"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.247981"},{"key":"e_1_3_4_7_2","volume-title":"GeneReviews((R))","author":"Sparks S. E.","year":"1993","unstructured":"S. E. Sparks, D. M. Krasnewich, \"Congenital disorders of N-linked glycosylation and multiple pathway overview\" in GeneReviews((R)), M. P. Adam , Eds. (Seattle, WA, 1993)."},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.262438199"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914004107"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.065169"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","unstructured":"N. Hadar X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome. Eur. J. Hum. Genet. (2023) 10.1038\/s41431-022-01278-5.","DOI":"10.1038\/s41431-022-01278-5"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt607"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200311112"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607872103"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00399.2019"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfq325"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2005.01558.x"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2015.10.033"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abm8783"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00117"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10194501"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/4371252a"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(99)00069-1"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.3233\/CBM-130375"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1731"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200711151"},{"key":"e_1_3_4_27_2","first-page":"282","article-title":"Identification of Tn antigen O-GalNAc-expressing glycoproteins in human carcinomas using novel anti-Tn recombinant antibodies","volume":"30","author":"Matsumoto Y.","year":"2020","unstructured":"Y. Matsumoto , Identification of Tn antigen O-GalNAc-expressing glycoproteins in human carcinomas using novel anti-Tn recombinant antibodies. Glycobiology 30, 282\u2013300 (2020).","journal-title":"Glycobiology"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.115.5.1243"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)30236-3"},{"key":"e_1_3_4_30_2","first-page":"629","article-title":"IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1","volume":"118","author":"Suzuki H.","year":"2008","unstructured":"H. Suzuki , IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J. Clin. Invest. 118, 629\u2013639 (2008).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2018.05.016"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.252"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M114.039693"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020081208"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006609"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1627"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfz241"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011050464"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-014-2863-y"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00504"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.638309"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.01.033"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg9118"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031273"},{"key":"e_1_3_4_45_2","unstructured":"Varbank https:\/\/varbank.ccg.uni\u2010koeln.de\/varbank2."},{"key":"e_1_3_4_46_2","first-page":"7","article-title":"Detection of nonrandom X chromosome inactivation","author":"Thouin M. M.","year":"2003","unstructured":"M. M. Thouin, J. M. Giron, E. P. Hoffman, Detection of nonrandom X chromosome inactivation. Curr. Protoc. Hum. Genet. Chapter 9, Unit 9 7 (2003).","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12890"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwq168"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2211087120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:16:22Z","timestamp":1695287782000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2211087120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,22]]},"references-count":48,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2023,5,30]]}},"alternative-id":["10.1073\/pnas.2211087120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2211087120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,22]]},"assertion":[{"value":"2022-06-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2211087120"}}