X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome

Noam Hadar, Ruth Schreiber, Marina Eskin-Schwartz, Eyal Kristal, George Shubinsky, Galina Ling, Idan Cohen, Michael Geylis, Amit Nahum, Yuval Yogev, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)1101-1107
Number of pages7
JournalEuropean Journal of Human Genetics
Volume31
Issue number10
DOIs
StatePublished - 1 Oct 2023

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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