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

View ORCID ProfileEmily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan Schmit, 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, Malgorziata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, Jordan S. Orange
doi: https://doi.org/10.1101/825554
Emily M. Mace
1Department of Pediatrics, Columbia University Irving Medical Center, New York NY USA 10032
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  • ORCID record for Emily M. Mace
  • For correspondence: em3375@cumc.columbia.edu
Silke Paust
2Department of Immunology and Microbiology, Scripps Research Institute La Jolla CA USA
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Matilde I. Conte
1Department of Pediatrics, Columbia University Irving Medical Center, New York NY USA 10032
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Ryan M. Baxley
3Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455
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Megan Schmit
3Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455
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Malini Mukherjee
4Center for Human Immunobiology, Texas Children’s Hospital, Houston TX USA 77030
5Department of Pediatrics, Baylor College of Medicine Houston TX USA 77030
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Ashley E. Pezzi
4Center for Human Immunobiology, Texas Children’s Hospital, Houston TX USA 77030
5Department of Pediatrics, Baylor College of Medicine Houston TX USA 77030
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Jolanta Chmielowiec
6Program in Developmental Biology, Baylor College of Medicine; Center for Cell and Gene Therapy, Texas Children’s Hospital, and Houston Methodist Hospital, Baylor College of Medicine; Molecular and Cellular Biology Department, Baylor College of Medicine; Stem Cell and Regenerative Medicine Center, Baylor College of Medicine; McNair Medical Institute, Baylor College of Medicine, Houston TX 77030
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Swetha Tatineni
4Center for Human Immunobiology, Texas Children’s Hospital, Houston TX USA 77030
7Rice University, Houston TX USA 77005
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Ivan K. Chinn
5Department of Pediatrics, Baylor College of Medicine Houston TX USA 77030
8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Zeynep Coban Akdemir
8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Shalini N. Jhangiani
8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Donna M. Muzny
8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
9Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
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Asbjørg Stray-Pedersen
10Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo, Norway
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Rachel E. Bradley
11Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales
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Mo Moody
11Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales
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Philip P. Connor
11Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales
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Adrian G. Heaps
12Department of Virology Immunology, North Cumbria University Hospitals, Carlisle, UK
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Colin Steward
13Department of Paediatric Haematology, Oncology and Bone Marrow Transplantation, Bristol Royal Hospital for Children, Bristol, UK
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Pinaki P. Banerjee
4Center for Human Immunobiology, Texas Children’s Hospital, Houston TX USA 77030
5Department of Pediatrics, Baylor College of Medicine Houston TX USA 77030
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Richard A. Gibbs
8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Malgorziata Borowiak
6Program in Developmental Biology, Baylor College of Medicine; Center for Cell and Gene Therapy, Texas Children’s Hospital, and Houston Methodist Hospital, Baylor College of Medicine; Molecular and Cellular Biology Department, Baylor College of Medicine; Stem Cell and Regenerative Medicine Center, Baylor College of Medicine; McNair Medical Institute, Baylor College of Medicine, Houston TX 77030
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James R. Lupski
5Department of Pediatrics, Baylor College of Medicine Houston TX USA 77030
8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
9Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
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Stephen Jolles
11Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales
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Anja K. Bielinsky
3Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455
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Jordan S. Orange
1Department of Pediatrics, Columbia University Irving Medical Center, New York NY USA 10032
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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 novel cause of NKD resulting from compound heterozygous mutations in 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. By modeling MCM10 deficiency in human NK cell lines and primary NK cell precursors, we demonstrate that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function.

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Posted November 02, 2019.
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Human NK cell deficiency as a result of biallelic mutations in MCM10
Emily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan Schmit, 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, Malgorziata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, Jordan S. Orange
bioRxiv 825554; doi: https://doi.org/10.1101/825554
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Human NK cell deficiency as a result of biallelic mutations in MCM10
Emily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan Schmit, 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, Malgorziata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, Jordan S. Orange
bioRxiv 825554; doi: https://doi.org/10.1101/825554

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