X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome

Area of Science:

• Genetics
• Hematology
• Immunology

Background:

• Hemolytic-uremic syndrome (HUS) is a leading cause of acute kidney injury in children, often linked to infections.
• Typical HUS involves Shiga toxin-producing E. coli, while atypical HUS (aHUS) has genetic origins with incompletely understood mechanisms.
• Streptococcus pneumoniae-induced HUS (pHUS) involves bacterial neuraminidase A exposing T antigens on erythrocytes, initiating complement-mediated thrombotic microangiopathy.

Purpose of the Study:

• To investigate the molecular basis of a novel X-linked form of atypical hemolytic-uremic syndrome (aHUS).
• To identify the genetic cause and elucidate the pathogenic mechanism of this aHUS subtype.
• To explore potential shared pathways between aHUS and pHUS.

Main Methods:

• Genetic studies to identify mutations in aHUS patients.
• Analysis of erythrocyte surface T antigen expression in affected individuals.
• Investigation of the complement pathway activation in relation to T antigen exposure.

Main Results:

• A de novo missense mutation in C1GALT1C1 (c.266C>T, p.(T89I)) was identified as the cause of a novel X-linked aHUS.
• This mutation affects the T-synthase chaperone, leading to exposed T antigens on erythrocytes.
• The exposed T antigen triggers thrombotic microangiopathy via the lectin-complement pathway, similar to pHUS.

Conclusions:

• A novel X-linked aHUS is caused by a C1GALT1C1 mutation leading to T antigen exposure and complement activation.
• This study delineates a shared molecular mechanism between aHUS and pHUS, mediated by the lectin-complement pathway.
• The findings suggest potential therapeutic strategies targeting this shared pathway for both aHUS and pHUS.