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

J Clin Invest. 2020 Oct 1;130(10):5272-5286. doi: 10.1172/JCI134966.

Emily M Mace ¹, Silke Paust ², Matilde I Conte ¹, Ryan M Baxley ³, Megan M Schmit ³, Sagar L Patil ¹, Nicole C Guilz ¹, Malini Mukherjee ⁴ ⁵, Ashley E Pezzi ⁴ ⁵, Jolanta Chmielowiec ⁶ ⁷, Swetha Tatineni ⁵ ⁸, Ivan K Chinn ⁵ ⁹, Zeynep Coban Akdemir ⁹, Shalini N Jhangiani ⁹ ¹⁰, Donna M Muzny ⁹ ¹⁰, Asbjørg Stray-Pedersen ¹¹, Rachel E Bradley ¹², Mo Moody ¹², Philip P Connor ¹², Adrian G Heaps ¹³, Colin Steward ¹⁴, Pinaki P Banerjee ⁴ ⁵, Richard A Gibbs ⁹ ¹⁰, Malgorzata Borowiak ⁶ ⁷ ¹⁵ ¹⁶, James R Lupski ⁵ ⁹ ¹⁰ ¹⁷, Stephen Jolles ¹², Anja K Bielinsky ³, Jordan S Orange ¹

Affiliations

1 Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.
2 Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California, USA.
3 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
4 Center for Human Immunobiology, Texas Children's Hospital, Houston, Texas, USA.
5 Department of Pediatrics.
6 Center for Cell and Gene Therapy, and.
7 Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, Texas, USA.
8 Department of BioSciences, Rice University, Houston, Texas, USA.
9 Department of Molecular and Human Genetics and.
10 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
11 Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo, Norway.
12 Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales.
13 Department of Virology and Immunology, North Cumbria University Hospitals, Carlisle, United Kingdom.
14 Department of Paediatric Haematology, Oncology and Bone Marrow Transplantation, Bristol Royal Hospital for Children, Bristol, United Kingdom.
15 Adam Mickiewicz University, Poznan, Poland.
16 McNair Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
17 Texas Children's Hospital, Houston, Texas, USA.

PMID: 32865517 DOI: 10.1172/JCI134966

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 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.

Keywords

Genetic diseases; Immunology; NK cells.

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