NK cell defects in X-linked pigmentary reticulate disorder

• DOI: 10.1172/jci.insight.125688
• Publication Date: 2019-10-31T15:01:33Z
• Authors: Petro Starokadomskyy; Katelynn M. Wilton; Konrad Krzewski; Adam Lopez; Luis Sifuentes-Do...; Brittany Overlee; Qing Chen; Ann Ray; Aleksandra Gil-Kr...; Mary Peterson; Lisa N. Kinch; Luis Rohena; Eyal Grunebaum; Andrew R. Zinn; Nick V. Grishin; Daniel D. Billadeau; Ezra Burstein
• Keywords: Reticulate

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The caused an intronic mutation POLA1, the gene encoding catalytic subunit of DNA polymerase-α (Pol-α), which responsible for Okazaki fragment synthesis during replication. Reduced POLA1 expression this condition triggers spontaneous type I interferon expression, can be linked to autoinflammatory manifestations disease. However, history as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity decreased numbers cells, particularly differentiated, stage V, cells (CD3-CD56dim). This phenotype reminiscent hypomorphic mutations MCM4, encodes component minichromosome maintenance (MCM) helicase complex functionally Pol-α replication process. We find deficiency leads MCM4 depletion both impair natural cytotoxicity show due defect lytic granule polarization. Altogether, our study provides mechanistic connections between MCM demonstrates their relevance function.