Human NK cell deficiency as a result of biallelic mutations in MCM10
Emily M. Mace, … , Anja K. Bielinsky, Jordan S. Orange
Emily M. Mace, … , Anja K. Bielinsky, Jordan S. Orange
Published August 31, 2020
Citation Information: J Clin Invest. 2020;130(10):5272-5286. https://doi.org/10.1172/JCI134966.
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Research Article Immunology

Human NK cell deficiency as a result of biallelic mutations in MCM10

Abstract

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage–response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

Authors

Emily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan M. Schmit, Sagar L. Patil, Nicole C. Guilz, Malini Mukherjee, Ashley E. Pezzi, Jolanta Chmielowiec, Swetha Tatineni, Ivan K. Chinn, Zeynep Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Asbjørg Stray-Pedersen, Rachel E. Bradley, Mo Moody, Philip P. Connor, Adrian G. Heaps, Colin Steward, Pinaki P. Banerjee, Richard A. Gibbs, Malgorzata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, Jordan S. Orange

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Figure 1

Decreased frequency of peripheral blood NK cells with overrepresentation of the CD56bright subset in an individual with compound heterozygous mutations in MCM10.

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Decreased frequency of peripheral blood NK cells with overrepresentation...
Severe CMV infection in the male proband born to healthy parents led to evaluation of peripheral blood NK cells and whole exome sequencing of the proband and his immediate family. (A) Flow cytometric analysis of peripheral blood NK cells from a representative healthy donor (left) and the proband (right). NK cells are defined as CD56+CD3−. The relative frequency of CD56bright NK cells within the NK cell subset is defined by density of CD56 staining (histograms). (B) Whole exome sequencing identified compound heterozygous mutations that were rare and predicted to be damaging with familial segregation. (C) Location of identified variants relative to MCM10 domains. Dashed line indicates previously defined NLS (32). NTD, N-terminal domain; ID, internal domain; CTD, C-terminal domain.