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

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

doi:10.1172/jci134966

Cited by 46 publications

(77 citation statements)

References 58 publications

(100 reference statements)

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“…1c). Consistently, RPE-1 cells homozygous for this variant showed stable MCM10 expression, although analyses of proliferation and sensitivity to ultra-violet (UV) light demonstrated that this allele is hypomorphic 12 .…”

Section: Resultsmentioning

confidence: 93%

“…Compound heterozygous MCM10 variants were identified in unrelated patients that presented with NKD or fetal RCM with thymic and splenic hypoplasia (Table 1; all genetic notation is in reference to MCM10 transcript NM_018518.5). Clinical and genetic analysis of the NKD patient and family was recently described 12 . The NKD-associated variants were identified in a single-family and included one missense (c.1276 C > T, p.R426C) and one nonsense variant (c.1744C > T, p.R582X).…”

Section: Resultsmentioning

confidence: 99%

“…For many years these observations constituted the only examples of MCM10-associated human disease. Recently, we identified human germline MCM10 variants in two unrelated families that were associated with distinct phenotypes: natural killer (NK) cell deficiency (NKD) 12 and restrictive cardiomyopathy (RCM) associated with thymic and splenic hypoplasia. Both of these conditions appear to be the result of compound heterozygous MCM10 variants.…”

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confidence: 99%

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Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

et al. 2021

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Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

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“… 125 ), MCM10 (ref. 126 ) and FCGR3A 127 . The first six genes affect NK cell development or maturation, with resulting low total NK cell numbers and specific defects affecting NK cell subsets.…”

Section: Nk Cell Deficiencies and Infectionsmentioning

confidence: 97%

Natural killer cells in antiviral immunity

2021

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Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue-resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive-like NK cell expansions as well as the appearance of CD56 − NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) giving rise to coronavirus disease 2019 (COVID-19).

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“…Recently-reported gene defects have been found for most categories of inborn errors of immunity, including novel causes of: SCID ( PAX1 [ 5 , 6 ], SLP76 [ 7 ]); CID ( MCM10 [ 8 ], IL6ST [ 9 – 11 ]); Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]); Autoinflammatory diseases ( SOCS1 [ 20 – 22 ], TET2 [ 23 ], CEBPE [ 24 ], CDC42 [ 33 – 39 ], LSM11 , RNU7–1 [ 32 ], STAT2 [ 40 , 41 ], RIPK1 [ 42 , 43 ], NCKAP1L [ 44 – 46 ]), UBA1 (somatic mutations) [ 47 ]; and Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ). …”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

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

Cited by 46 publications

References 58 publications

Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

Natural killer cells in antiviral immunity

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

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