Defective sugar chains trigger genetic syndrome

26/05/2023

Cologne researchers identify a novel chaperonopathy causing altered protein O-glycosylation. This discovery will promote a better understanding of the role of complex O-glycans in human health and disease.

Figure 1: (A) Schematic of O-glycan biosynthesis. Cosmc is an ER-localized molecular chaperone required for T-synthase function. T-synthase is critical for the generation of normal elongated O-glycans at serine, threonine, and tyrosine (S/T/Y) residues in glycoproteins. In the absence of functional Cosmc, T-synthase remains inactive and is degraded, resulting in truncated O-glycans. (B) Visualization of the transmembrane topology of full-length Cosmc protein. The red-filled alanine residue is mutated in patients M1, M2, F1, and F2. The orange-filled residues were affected by somatic mutations in previously reported patients with Tn syndrome. The light blue residue was affected in a recent single case publication of a patient carrying a de novo variant (c.266C>T; p.Thr89Ile) in C1GALT1C1 (11). Protein visualization modified from Protter output (12). - PNAS May 22, 2023 / 120(22)e2211087120 - https://doi.org/10.1073/pnas.2211087120
Dr. Florian Erger abd PD Dr. Bodo Beck (Foto: Michael Wodak)

The function of almost all known proteins in humans is largely dependent on different, usually multi-step maturation processes within the cell. One of these processes involves the attachment of complex sugar chains, which can, for example, increase protein stability or exert a signaling function.

An interdisciplinary research group at the University of Cologne/University Hospital of Cologne has now identified a defect in this system as the cause of a severe syndrome disease in two patients. They are publishing their findings this week (May 23, 2023) in the prestigious journal The Proceedings of the National Academy of Sciences (PNAS) with following title Germline C1GALT1C1 mutation causes a multisystem chaperonopathy - doi: 10.1073/pnas.2211087120

The research group for "Rare and Hereditary Kidney Diseases" led by Dr. Florian Erger and PD Dr. Bodo Beck at the Institute of Human Genetics and collaborators from the Clinic of Pediatrics and Adolescent Medicine, the Cologne Center for Genomics (CCG) and the Center for Molecular Medicine Cologne (CMMC) succeeded in discovering a new gene defect in a national and international collaboration with the Institute of Human Genetics of the University Hospital Aachen and the National Center for Functional Glycomics of Harvard University (Boston, USA).

The researchers were able to show, mutations in the X-linked gene C1GALT1C1 lead to growth retardation, intellectual developmental disorder, bleeding tendency, immune deficiency and an increased risk of sudden severe episodes of kidney failure in male affected individuals. However, this acute kidney weakness can be treated with a special drug and usually quickly returned to full normal. Patients are spared dialysis or kidney transplantation.

The research work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Clinical Research Group "KFO 329: Molecular Mechanisms of Podocyte Diseases" a joint enterprise of the Medical Faculty and the Faculty of Mathematics and Natural Sciences of the University of Cologne.

Publication
Germline C1GALT1C1 mutation causes a multisystem chaperonopathy.
Erger F, Aryal RP, Reusch B, Matsumoto Y, Meyer R, Zeng J, Knopp C, Noel M, Muerner L, Wenzel A, Kohl S, Tschernoster N, Rappl G, Rouvet I, Schröder-Braunstein J, Seibert FS, Thiele H, Häusler MG, Weber LT, Büttner-Herold M, Elbracht M, Cummings SF, Altmüller J, Habbig S, Cummings RD, Beck BB. Proc Natl Acad Sci U S A. 2023 May 30;120(22):e2211087120.  - doi: 10.1073/pnas.2211087120.
PMID: 37216524.

Scientific Contact
Dr. Florian Erger (florian.erger[at]uk-koeln.de)and PD Dr. Bodo Beck (bodo.beck[at]uk-koeln.de)
Institute of Human Genetics, University Hospital Cologne, Faculty of Medicine, University of Cologne
Center for Molecular Medicine Cologne, University of Cologne
 

Press Release - University Hospital Cologne

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