NK cell defects in X-linked pigmentary reticulate disorder

JCI Insight. 2019 Nov 1;4(21):e125688. doi: 10.1172/jci.insight.125688.

Petro Starokadomskyy ¹, Katelynn M Wilton ², Konrad Krzewski ³, Adam Lopez ¹, Luis Sifuentes-Dominguez ⁴, Brittany Overlee ², Qing Chen ¹ ⁵, Ann Ray ⁶, Aleksandra Gil-Krzewska ³, Mary Peterson ⁷, Lisa N Kinch ⁸, Luis Rohena ⁹, Eyal Grunebaum ¹⁰, Andrew R Zinn ¹ ¹¹, Nick V Grishin ⁸ ¹² ¹³, Daniel D Billadeau ², Ezra Burstein ¹ ¹⁴

Affiliations

1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2 Department of Immunology and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
3 Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA.
4 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5 Department of Surgery, Tongji University affiliated Tongji Hospital, Shanghai, China.
6 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7 Molecular and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, USA.
8 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
9 Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.
10 Division of Immunology and Allergy and Department of Pediatrics, Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
11 Eugene McDermott Center for Human Growth and Development.
12 Department of Biochemistry.
13 Department of Biophysics, and.
14 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

PMID: 31672938 DOI: 10.1172/jci.insight.125688

Abstract

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

Keywords

Infectious disease; Inflammation; Innate immunity; Monogenic diseases; NK cells.

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