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X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome

European Journal of Human Genetics volume 31, pages 1101–1107 (2023)Cite this article

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Abstract

Hemolytic-uremic syndrome (HUS), mostly secondary to infectious diseases, is a common cause of acute kidney injury in children. It is characterized by progressive acute kidney failure due to severe thrombotic microangiopathy, associated with nonimmune, Coombs-negative hemolytic anemia and thrombocytopenia. HUS is caused mostly by Shiga toxin-producing E. Coli, and to a lesser extent by Streptococcus pneumonia. In Streptococcus pneumonia HUS (pHUS), bacterial neuraminidase A exposes masked O-glycan sugar residues on erythrocytes, known as the T antigen, triggering a complement cascade causing thrombotic microangiopathy. Atypical HUS (aHUS) is a life-threatening genetic form of the disease, whose molecular mechanism is only partly understood. Through genetic studies, we demonstrate a novel X-linked form of aHUS that is caused by a de-novo missense mutation in C1GALT1C1:c.266 C > T,p.(T89I), encoding a T-synthase chaperone essential for the proper formation and incorporation of the T antigen on erythrocytes. We demonstrate the presence of exposed T antigen on the surface of mutant erythrocytes, causing aHUS in a mechanism similar to that suggested in pHUS. Our findings suggest that both aHUS caused by mutated C1GALT1C1 and pHUS are mediated by the lectin-complement-pathway, not comprehensively studied in aHUS. We thus delineate a shared molecular basis of aHUS and pHUS, highlighting possible therapeutic opportunities.

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Fig. 1: Pedigree and molecular genetics.
Fig. 2: Tn-antigen detection using flow cytometry.
Fig. 3: Hemagglutination of erythrocytes’ T-antigen.
Fig. 4: Proposed mechanism.

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Data availability

Data support the findings of this study, including the WES raw data, are available from the corresponding author upon request (O.S.B) upon reasonable request.

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Funding

The study was funded by the Morris Kahn Family Foundation, the Israel Science Foundation (Grant no. 2034/18) awarded to OSB, and the National Knowledge Center for Rare/Orphan Diseases of the Israel Ministry of Science, Technology and Space, at Ben-Gurion University of the Negev and Soroka Medical Center, Beer-Sheva, Israel. The work of GS is supported in part by the Israel Ministry of Aliyah and Integration.

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Authors and Affiliations

  1. The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

    Noam Hadar, Marina Eskin-Schwartz, Yuval Yogev & Ohad S. Birk

  2. Pediatric Nephrology Clinic and Pediatric Department A, Soroka University Medical Center, Beer-Sheva, Israel

    Ruth Schreiber, Michael Geylis & Amit Nahum

  3. Genetics Institute, Soroka University Medical Center, Beer-Sheva, Israel

    Marina Eskin-Schwartz & Ohad S. Birk

  4. Pediatric Ambulatory Unit, Soroka University Medical Center, Beer-Sheva, Israel

    Eyal Kristal & Galina Ling

  5. Flow Cytometry Unit, Soroka University Medical Center, Beer-Sheva, Israel

    George Shubinsky

  6. The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheva, Israel

    Idan Cohen & Ohad S. Birk

  7. The Primary Immunodeficiency Research Laboratory and Pediatric Department A, Soroka University Medical Center, Beer Sheva, Israel

    Amit Nahum

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  1. Noam Hadar
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Contributions

The manuscript was written by NH with the assistance of RS, EK, YY and OSB. NH performed bioinformatics and WES analysis. NH and GS designed and performed experiments. Microscopy was performed with the assistance of IC. RS, MES, EK, GL, MG and AN contributed to clinical evaluation of the patient. The study was supervised by OSB.

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Correspondence to Ohad S. Birk.

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The participants of this study provided written informed consent according to a protocol approved by the Soroka Medical Center institutional review board and by the Israel National Committee for Human Genetic Studies, in adherence with the Helsinki principles (ID5071G).

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Hadar, N., Schreiber, R., Eskin-Schwartz, M. et al. X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome. Eur J Hum Genet 31, 1101–1107 (2023). https://doi.org/10.1038/s41431-022-01278-5

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