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

TitleHuman NK cell deficiency as a result of biallelic mutations in MCM10.
Publication TypeJournal Article
Year of Publication2020
AuthorsMace, EM, Paust, S, Conte, MI, Baxley, RM, Schmit, MM, Patil, SL, Guilz, NC, Mukherjee, M, Pezzi, AE, Chmielowiec, J, Tatineni, S, Chinn, IK, Akdemir, ZCoban, Jhangiani, SN, Muzny, DM, Stray-Pedersen, A, Bradley, RE, Moody, M, Connor, PP, Heaps, AG, Steward, C, Banerjee, PP, Gibbs, RA, Borowiak, M, Lupski, JR, Jolles, S, Bielinsky, AK, Orange, JS
JournalJ Clin Invest
Date Published2020 Oct 01
KeywordsAlleles, Cell Cycle Checkpoints, Cell Differentiation, Cell Line, Codon, Nonsense, DNA Damage, Fatal Outcome, Female, Gene Knockdown Techniques, Heterozygote, Humans, Induced Pluripotent Stem Cells, Infant, Killer Cells, Natural, Male, Minichromosome Maintenance Proteins, Models, Immunological, Mutation, Mutation, Missense, Pedigree, Primary Immunodeficiency Diseases

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.

Alternate JournalJ Clin Invest
PubMed ID32865517
PubMed Central IDPMC7524476
Grant ListT32 GM008244 / GM / NIGMS NIH HHS / United States
R01 GM134681 / GM / NIGMS NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
UL1 TR002494 / TR / NCATS NIH HHS / United States
R01 GM074917 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01 AI137275 / AI / NIAID NIH HHS / United States
T32 DK007647 / DK / NIDDK NIH HHS / United States
TL1 TR002493 / TR / NCATS NIH HHS / United States
T32 CA009138 / CA / NCI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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