Cover Image

Germline C1GALT1C1 mutation causes a multisystem chaperonopathy

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...

Full description

Saved in:
Bibliographic Details
Main Authors: Erger, Florian (Author) , Aryal, Rajindra P. (Author) , Reusch, Björn (Author) , Matsumoto, Yasuyuki (Author) , Meyer, Robert (Author) , Zeng, Junwei (Author) , Knopp, Cordula (Author) , Noel, Maxence (Author) , Muerner, Lukas (Author) , Wenzel, Andrea (Author) , Kohl, Stefan (Author) , Tschernoster, Nikolai (Author) , Rappl, Gunter (Author) , Rouvet, Isabelle (Author) , Schröder-Braunstein, Jutta (Author) , Seibert, Felix S. (Author) , Thiele, Holger (Author) , Häusler, Martin G. (Author) , Weber, Lutz T. (Author) , Büttner-Herold, Maike (Author) , Elbracht, Miriam (Author) , Cummings, Sandra F. (Author) , Altmüller, Janine (Author) , Habbig, Sandra (Author) , Cummings, Richard D. (Author) , Beck, Bodo B. (Author)
Format: Article (Journal)
Language:English
Published: May 30, 2023
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2023, Volume: 120, Issue: 22, Pages: 1-11
ISSN:1091-6490
DOI:10.1073/pnas.2211087120
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.2211087120
Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/doi/10.1073/pnas.2211087120
Get full text
Author Notes:Florian Erger, Rajindra P. Aryal, Björn Reusch, Yasuyuki Matsumoto, Robert Meyer, Junwei Zeng, Cordula Knopp, Maxence Noel, Lukas Muerner, Andrea Wenzel, Stefan Kohl, Nikolai Tschernoster, Gunter Rappl, Isabelle Rouvet, Jutta Schröder-Braunstein, Felix S. Seibert, Holger Thiele, Martin G. Häusler, Lutz T. Weber, Maike Büttner-Herold, Miriam Elbracht, Sandra F. Cummings, Janine Altmüller, Sandra Habbig, Richard D. Cummings, and Bodo B. Beck

MARC

LEADER 00000caa a2200000 c 4500
001 186151672X
003 DE-627
005 20240307051053.0
007 cr uuu---uuuuu
008 231011s2023 xx |||||o 00| ||eng c
024 7 |a 10.1073/pnas.2211087120  |2 doi 
035 |a (DE-627)186151672X 
035 |a (DE-599)KXP186151672X 
035 |a (OCoLC)1425210448 
040 |a DE-627  |b ger  |c DE-627  |e rda 
041 |a eng 
084 |a 33  |2 sdnb 
100 1 |a Erger, Florian  |d 1987-  |e VerfasserIn  |0 (DE-588)1143256581  |0 (DE-627)1002671353  |0 (DE-576)494976322  |4 aut 
245 1 0 |a Germline C1GALT1C1 mutation causes a multisystem chaperonopathy  |c Florian Erger, Rajindra P. Aryal, Björn Reusch, Yasuyuki Matsumoto, Robert Meyer, Junwei Zeng, Cordula Knopp, Maxence Noel, Lukas Muerner, Andrea Wenzel, Stefan Kohl, Nikolai Tschernoster, Gunter Rappl, Isabelle Rouvet, Jutta Schröder-Braunstein, Felix S. Seibert, Holger Thiele, Martin G. Häusler, Lutz T. Weber, Maike Büttner-Herold, Miriam Elbracht, Sandra F. Cummings, Janine Altmüller, Sandra Habbig, Richard D. Cummings, and Bodo B. Beck 
264 1 |c May 30, 2023 
300 |b Illustrationen 
300 |a 11 
336 |a Text  |b txt  |2 rdacontent 
337 |a Computermedien  |b c  |2 rdamedia 
338 |a Online-Ressource  |b cr  |2 rdacarrier 
500 |a Online veröffentlicht: 22. Mai 2023 
500 |a Gesehen am 11.10.2023 
520 |a 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. 
700 1 |a Aryal, Rajindra P.  |e VerfasserIn  |4 aut 
700 1 |a Reusch, Björn  |e VerfasserIn  |4 aut 
700 1 |a Matsumoto, Yasuyuki  |e VerfasserIn  |4 aut 
700 1 |a Meyer, Robert  |e VerfasserIn  |4 aut 
700 1 |a Zeng, Junwei  |e VerfasserIn  |4 aut 
700 1 |a Knopp, Cordula  |e VerfasserIn  |4 aut 
700 1 |a Noel, Maxence  |e VerfasserIn  |4 aut 
700 1 |a Muerner, Lukas  |e VerfasserIn  |4 aut 
700 1 |a Wenzel, Andrea  |e VerfasserIn  |4 aut 
700 1 |a Kohl, Stefan  |e VerfasserIn  |4 aut 
700 1 |a Tschernoster, Nikolai  |e VerfasserIn  |4 aut 
700 1 |a Rappl, Gunter  |e VerfasserIn  |4 aut 
700 1 |a Rouvet, Isabelle  |e VerfasserIn  |4 aut 
700 1 |a Schröder-Braunstein, Jutta  |e VerfasserIn  |0 (DE-588)1100387021  |0 (DE-627)859344096  |0 (DE-576)469677821  |4 aut 
700 1 |a Seibert, Felix S.  |e VerfasserIn  |4 aut 
700 1 |a Thiele, Holger  |e VerfasserIn  |4 aut 
700 1 |a Häusler, Martin G.  |e VerfasserIn  |4 aut 
700 1 |a Weber, Lutz T.  |e VerfasserIn  |4 aut 
700 1 |a Büttner-Herold, Maike  |e VerfasserIn  |4 aut 
700 1 |a Elbracht, Miriam  |e VerfasserIn  |4 aut 
700 1 |a Cummings, Sandra F.  |e VerfasserIn  |4 aut 
700 1 |a Altmüller, Janine  |e VerfasserIn  |4 aut 
700 1 |a Habbig, Sandra  |e VerfasserIn  |4 aut 
700 1 |a Cummings, Richard D.  |e VerfasserIn  |4 aut 
700 1 |a Beck, Bodo B.  |e VerfasserIn  |4 aut 
773 0 8 |i Enthalten in  |a National Academy of Sciences (Washington, DC)  |t Proceedings of the National Academy of Sciences of the United States of America  |d Washington, DC : National Acad. of Sciences, 1915  |g 120(2023), 22, Artikel-ID e2211087120, Seite 1-11  |h Online-Ressource  |w (DE-627)254235379  |w (DE-600)1461794-8  |w (DE-576)073260509  |x 1091-6490  |7 nnas 
773 1 8 |g volume:120  |g year:2023  |g number:22  |g elocationid:e2211087120  |g pages:1-11  |g extent:11  |a Germline C1GALT1C1 mutation causes a multisystem chaperonopathy 
856 4 0 |u https://doi.org/10.1073/pnas.2211087120  |x Verlag  |x Resolving-System  |z lizenzpflichtig  |3 Volltext 
856 4 0 |u https://www.pnas.org/doi/10.1073/pnas.2211087120  |x Verlag  |z lizenzpflichtig  |3 Volltext 
951 |a AR 
992 |a 20231011 
993 |a Article 
994 |a 2023 
998 |g 1100387021  |a Schröder-Braunstein, Jutta  |m 1100387021:Schröder-Braunstein, Jutta  |d 910000  |d 911600  |e 910000PS1100387021  |e 911600PS1100387021  |k 0/910000/  |k 1/910000/911600/  |p 15 
999 |a KXP-PPN186151672X  |e 4383911250 
BIB |a Y 
SER |a journal 
JSO |a {"note":["Online veröffentlicht: 22. Mai 2023","Gesehen am 11.10.2023"],"recId":"186151672X","id":{"doi":["10.1073/pnas.2211087120"],"eki":["186151672X"]},"title":[{"title":"Germline C1GALT1C1 mutation causes a multisystem chaperonopathy","title_sort":"Germline C1GALT1C1 mutation causes a multisystem chaperonopathy"}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"origin":[{"dateIssuedDisp":"May 30, 2023","dateIssuedKey":"2023"}],"language":["eng"],"relHost":[{"recId":"254235379","corporate":[{"display":"National Academy of Sciences","role":"aut","roleDisplay":"VerfasserIn"}],"titleAlt":[{"title":"PNAS online"},{"title":"PNAS"}],"pubHistory":["1.1915 -"],"type":{"media":"Online-Ressource","bibl":"periodical"},"origin":[{"publisher":"National Acad. of Sciences","dateIssuedDisp":"1915-","dateIssuedKey":"1915","publisherPlace":"Washington, DC"}],"language":["eng"],"physDesc":[{"extent":"Online-Ressource"}],"part":{"text":"120(2023), 22, Artikel-ID e2211087120, Seite 1-11","volume":"120","issue":"22","extent":"11","year":"2023","pages":"1-11"},"note":["Gesehen am 09.03.2022"],"disp":"National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America","id":{"issn":["1091-6490"],"zdb":["1461794-8"],"eki":["254235379"]},"title":[{"title":"Proceedings of the National Academy of Sciences of the United States of America","title_sort":"Proceedings of the National Academy of Sciences of the United States of America"}]}],"person":[{"family":"Erger","roleDisplay":"VerfasserIn","display":"Erger, Florian","role":"aut","given":"Florian"},{"display":"Aryal, Rajindra P.","role":"aut","given":"Rajindra P.","roleDisplay":"VerfasserIn","family":"Aryal"},{"given":"Björn","role":"aut","display":"Reusch, Björn","roleDisplay":"VerfasserIn","family":"Reusch"},{"given":"Yasuyuki","display":"Matsumoto, Yasuyuki","role":"aut","roleDisplay":"VerfasserIn","family":"Matsumoto"},{"family":"Meyer","roleDisplay":"VerfasserIn","given":"Robert","role":"aut","display":"Meyer, Robert"},{"role":"aut","display":"Zeng, Junwei","given":"Junwei","family":"Zeng","roleDisplay":"VerfasserIn"},{"given":"Cordula","display":"Knopp, Cordula","role":"aut","family":"Knopp","roleDisplay":"VerfasserIn"},{"family":"Noel","roleDisplay":"VerfasserIn","given":"Maxence","display":"Noel, Maxence","role":"aut"},{"role":"aut","display":"Muerner, Lukas","given":"Lukas","family":"Muerner","roleDisplay":"VerfasserIn"},{"display":"Wenzel, Andrea","role":"aut","given":"Andrea","family":"Wenzel","roleDisplay":"VerfasserIn"},{"family":"Kohl","roleDisplay":"VerfasserIn","role":"aut","display":"Kohl, Stefan","given":"Stefan"},{"family":"Tschernoster","roleDisplay":"VerfasserIn","role":"aut","display":"Tschernoster, Nikolai","given":"Nikolai"},{"given":"Gunter","role":"aut","display":"Rappl, Gunter","family":"Rappl","roleDisplay":"VerfasserIn"},{"display":"Rouvet, Isabelle","role":"aut","given":"Isabelle","roleDisplay":"VerfasserIn","family":"Rouvet"},{"given":"Jutta","role":"aut","display":"Schröder-Braunstein, Jutta","family":"Schröder-Braunstein","roleDisplay":"VerfasserIn"},{"roleDisplay":"VerfasserIn","family":"Seibert","display":"Seibert, Felix S.","role":"aut","given":"Felix S."},{"role":"aut","display":"Thiele, Holger","given":"Holger","family":"Thiele","roleDisplay":"VerfasserIn"},{"role":"aut","display":"Häusler, Martin G.","given":"Martin G.","roleDisplay":"VerfasserIn","family":"Häusler"},{"family":"Weber","roleDisplay":"VerfasserIn","given":"Lutz T.","role":"aut","display":"Weber, Lutz T."},{"given":"Maike","display":"Büttner-Herold, Maike","role":"aut","family":"Büttner-Herold","roleDisplay":"VerfasserIn"},{"given":"Miriam","role":"aut","display":"Elbracht, Miriam","roleDisplay":"VerfasserIn","family":"Elbracht"},{"family":"Cummings","roleDisplay":"VerfasserIn","display":"Cummings, Sandra F.","role":"aut","given":"Sandra F."},{"roleDisplay":"VerfasserIn","family":"Altmüller","display":"Altmüller, Janine","role":"aut","given":"Janine"},{"roleDisplay":"VerfasserIn","family":"Habbig","role":"aut","display":"Habbig, Sandra","given":"Sandra"},{"roleDisplay":"VerfasserIn","family":"Cummings","given":"Richard D.","role":"aut","display":"Cummings, Richard D."},{"family":"Beck","roleDisplay":"VerfasserIn","display":"Beck, Bodo B.","role":"aut","given":"Bodo B."}],"physDesc":[{"noteIll":"Illustrationen","extent":"11 S."}],"name":{"displayForm":["Florian Erger, Rajindra P. Aryal, Björn Reusch, Yasuyuki Matsumoto, Robert Meyer, Junwei Zeng, Cordula Knopp, Maxence Noel, Lukas Muerner, Andrea Wenzel, Stefan Kohl, Nikolai Tschernoster, Gunter Rappl, Isabelle Rouvet, Jutta Schröder-Braunstein, Felix S. Seibert, Holger Thiele, Martin G. Häusler, Lutz T. Weber, Maike Büttner-Herold, Miriam Elbracht, Sandra F. Cummings, Janine Altmüller, Sandra Habbig, Richard D. Cummings, and Bodo B. Beck"]}} 
SRT |a ERGERFLORIGERMLINEC13020 

Similar Items