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.
Bibliographical noteFunding Information:
This work was supported by NIH R01AI120989 (to JSO), NIH R01AI37275 (to EMM), NIH GM074917 (to AKB), NIH T32-CA009138 (to RMB), NIH National Center for Advancing Translational Sciences TL1R002493 and UL1TR002494 (MMS) and the University of Minnesota Imaging Centers, NIH Medical Scientist Training Program (MSTP) grant T32 GM008244 (to MMS), and National Science Center POLONEZ grant 2015/19/P/NZ3/03452 (to MB). JRL is supported in part by the NIH National Institute of Neurological Disorders and Stroke (R35NS105078) and the Nation- al Human Genome Research Institute/National Heart, Lung, and Blood Institute (UM1 HG006542 to the BHCMG). The authors wish to acknowledge Blake Heath, Jansen Smith, Laura Angelo, and Emily Haines for technical assistance with the development and experimentation on the humanized mouse model and Diane Yang for technical assistance with iPS cell generation and validation.