Human NK cell deficiency as a result of biallelic mutations in <i>MCM10</i>

Mace, Emily M.; Paust, Silke; Conte, Matilde Immacolata; Baxley, Ryan M.; Schmit, Megan; Mukherjee, Malini; Pezzi, Ashley E.; Chmielowiec, Jolanta; Tatineni, Swetha; Chinn, Iván K.; Akdemir, Zeynep Coban; Jhangiani, Shalini N.; Stray-Pedersen, Asbjørg; Bradley, Rachel E.; Moody, Mo; Connor, Philip; Heaps, Adrian; Steward, Colin G.; Banerjee, Pinaki P.; Gibbs, Richard A.; Borowiak, Malgorziata; Lupski, James R.; Jolles, Stephen; Bielinsky, Anja Katrin; Orange, Jordan S.

doi:10.1101/825554

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…Several bona fide NKD have been reported with mutations in genes relating to the DNA replication machinery. IRF8, MCM4, MCM10 and GINS1 deficiency all lead to selective loss of the CD56 dim subset and concomitant overrepresentation of the CD56 bright subset 50,51,52,53 . Especially the GINS1 mutation with selective effects on neutrophils and NK cells in terms of proliferation is relevant in this context 52,54 .…”

Section: Discussionmentioning

confidence: 99%

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Sohlberg

Pfefferle

Ask

et al. 2022

Blood

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Neutrophils have been suggested to play a critical role in terminal differentiation of NK cells. Whether this is a direct effect or a consequence of global immune changes with effects on NK cell homeostasis remains unknown. Here, we used high-resolution flow- and mass cytometry to examine NK cell repertoires in 64 patients with neutropenia and 27 healthy age- and gender-matched donors. A subgroup of patients with chronic neutropenia showed severely disrupted NK cell homeostasis manifested as increased frequencies of CD56bright NK cells and a lack of mature CD56dim NK cells. These immature NK cell repertoires were characterized by expression of proliferation/exhaustion markers Ki-67, Tim-3 and TIGIT and displayed blunted tumor target cell responses. Systems-level immune mapping revealed that the changes in immunophenotypes were confined to NK cells, leaving T cell differentiation intact. RNA sequencing of NK cells from these patients showed upregulation of a network of genes, including TNFSF9, CENPF, MKI67 and TOP2A, associated with apoptosis and the cell cycle, different from conventional CD56bright signatures. Profiling of 249 plasma proteins showed a coordinated enrichment of pathways related to apoptosis and cell turnover, which correlated with immature NK cell repertoires. Notably, most of these patients exhibited severe-grade neutropenia, suggesting that the profoundly altered NK cell homeostasis was connected to the severity of their underlying etiology. Hence, although our data suggests that neutrophils are dispensable for NK cell development and differentiation, some patients displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations.

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Section: Discussionmentioning

confidence: 99%

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Sohlberg

Pfefferle

Ask

et al. 2022

Blood

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“…To compare the MCM10 profiles to RIF1 profiles in a similar cell type, we generated two RIF1 KO clones in haploid ESCs (40,41) (42). These MCM10 mutations were previously shown to prevent its nuclear localization, causing de-stabilization of the replisome, reduced origin firing, genome instability and reduced cell proliferation (42,43). Taken together, we propose that MCM10 is a strong candidate for being a novel regulator of DNA replication timing.…”

Section: Mcm10 Is a Novel Regulator Of Dna Replication Timingmentioning

confidence: 96%

“…by means of a secondary mutation) impinge on RIF1 function. To compare the MCM10 profiles to RIF1 profiles in a similar cell type, we generated two RIF1 KO clones in haploid ESCs (40,41) (42). These MCM10 mutations were previously shown to prevent its nuclear localization, causing de-stabilization of the replisome, reduced origin firing, genome instability and reduced cell proliferation (42,43).…”

Section: Mcm10 Is a Novel Regulator Of Dna Replication Timingmentioning

confidence: 99%

Comprehensive analysis of DNA replication timing in genetic diseases and gene knockouts identifies MCM10 as a novel regulator of the replication program

Caballero

Rebelo

et al. 2021

Preprint

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Cellular proliferation depends on the accurate and timely replication of the genome. Several genetic diseases are caused by mutations in key DNA replication genes; however, it remains unclear whether these genes influence the normal program of DNA replication timing. Similarly, the factors that regulate DNA replication dynamics are poorly understood. To systematically identify trans-acting modulators of replication timing, we profiled replication in 184 cell lines from three cell types, encompassing 60 different gene knockouts or genetic diseases. Through a rigorous approach that considers the background variability of replication timing, we concluded that most samples displayed normal replication timing. However, mutations in two genes showed consistently abnormal replication timing. The first gene was RIF1, a known modulator of replication timing. The second was MCM10, a highly conserved member of the pre-replication complex. MCM10 mutant cells demonstrated replication timing variability comprising 46% of the genome and at different locations than RIF1 knockouts. Replication timing alterations in MCM10-mutant cells was predominantly comprised of replication initiation defects. Taken together, this study demonstrates the remarkable robustness of the human replication timing program and reveals MCM10 as a novel modulator of DNA replication timing.

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“…This cytotoxic function can be triggered through direct contact-dependent recognition via activating NK receptors (NKRs) or indirectly via engagement of the low affinity IgG receptor CD16 ( FcRγIIIa ), enabling antibody-dependent cellular cytotoxicity (ADCC). The crucial role NK cells play in the host defense against CMV is demonstrated by cases of severe and even fatal CMV infection among children with genetic defects leading to selective NK cell deficiency[4,5]. However, the fetal NK cell response to congenital CMV (cCMV) infection has not been characterized.…”

Section: Introductionmentioning

confidence: 99%

In Utero Activation of NK Cells in Congenital CMV Infection

Vaaben

Levan

Nguyen

et al. 2022

Preprint

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Background: Congenital cytomegalovirus (CMV) infection is the most common infectious cause of birth defects and neurological damage in newborns. Despite a well-established role for NK cells in control of CMV infection in older children and adults, it remains unknown whether fetal NK cells can sense and respond to CMV infection acquired in utero. Methods: Here, we investigate the impact of congenital CMV infection on the neonatal NK cell repertoire by assessing the frequency, phenotype, and functional profile of NK cells in cord blood samples from newborns with congenital CMV and from uninfected controls enrolled in a birth cohort of Ugandan mothers and infants. Results: We find that neonatal NK cells from congenitally CMV infected newborns show increased expression of cytotoxic mediators, signs of maturation and activation, and an expansion of mature CD56-negative NK cells, an NK cell subset associated with chronic viral infections in adults. Activation was particularly prominent in NK cell subsets expressing the Fcγ receptor CD16, indicating a role for antibody-mediated immunity against CMV in utero. Conclusion: These findings demonstrate that NK cells can be activated in utero and suggest that NK cells may be an important component of the fetal and infant immune response against CMV.

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

Cited by 4 publications

References 60 publications

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Comprehensive analysis of DNA replication timing in genetic diseases and gene knockouts identifies MCM10 as a novel regulator of the replication program

In Utero Activation of NK Cells in Congenital CMV Infection

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