Preponderance of CTLA4 Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif

Owen M. Siggs, Amanda Russell, Davinder Singh-Grewal, Melanie Wong, Pearl Chan, Maria E. Craig, Ted O'Loughlin, Michael Stormon, Christopher C. Goodnow

    Research output: Contribution to journalArticlepeer-review

    8 Citations (Scopus)


    One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of CTLA4. Here we describe a heterozygous de novo missense variant of CTLA4 in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of CTLA4 variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.

    Original languageEnglish
    Article number1544
    Number of pages6
    JournalFrontiers in Immunology
    Publication statusPublished - 23 Jul 2019


    • abatacept
    • autoimmune hepatitis
    • CTLA-4
    • CTLA4
    • de novo variant
    • ipilimumab
    • juvenile rheumatoid arthritis (JRA)


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