An update on gain-of-function mutations in primary immunodeficiency diseases

Purpose of review: Most primary immunodeficiencies described since 1952 were associated with loss-of-function defects. With the advent and popularization of unbiased next-generation sequencing diagnostic approaches followed by functional validation techniques, many gain-of-function mutations leading to immunodeficiency have also been identified. This review highlights the updates on pathophysiology mechanisms and new therapeutic approaches involving primary immunodeficiencies because of gain-of-function mutations. Recent findings: The more recent developments related to gain-of-function primary immunodeficiencies mostly involving increased infection susceptibility but also immune dysregulation and autoimmunity, were reviewed. Updates regarding pathophysiology mechanisms, different mutation types, clinical features, laboratory markers, current and potential new treatments on patients with caspase recruitment domain family member 11, signal transducer and activator of transcription 1, signal transducer and activator of transcription 3, phosphatidylinositol-4,5-biphosphate 3-kinase catalytic 110, phosphatidylinositol-4,5-biphosphate 3-kinase regulatory subunit 1, chemokine C-X-C motif receptor 4, sterile α motif domain containing 9-like, and nuclear factor κ-B subunit 2 gain-of-function mutations are reviewed for each disease. Summary: With the identification of gain-of-function mutations as a cause of immunodeficiency, new genetic pathophysiology mechanisms unveiled and new-targeted therapeutic approaches can be explored as potential rescue treatments for these diseases.

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