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

Ryan M. Baxley, Wendy Leung, Megan M. Schmit, Jacob Peter Matson, Lulu Yin, Marissa K. Oram, Liangjun Wang, John Taylor, Jack Hedberg, Colette B. Rogers, Adam J. Harvey, Debashree Basu, Jenny C. Taylor, Alistair T. Pagnamenta, Helene Dreau, Jude Craft, Elizabeth Ormondroyd, Hugh Watkins, Eric A. Hendrickson, Emily M. Mace, Jordan S. Orange, Hideki Aihara, Grant S. Stewart, Edward Blair, Jeanette Gowen Cook and Anja-Katrin Bielinsky ()
Additional contact information
Ryan M. Baxley: University of Minnesota
Wendy Leung: University of Minnesota
Megan M. Schmit: University of Minnesota
Jacob Peter Matson: University of North Carolina
Lulu Yin: University of Minnesota
Marissa K. Oram: University of Minnesota
Liangjun Wang: University of Minnesota
John Taylor: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Jack Hedberg: University of Minnesota
Colette B. Rogers: University of Minnesota
Adam J. Harvey: University of Minnesota
Debashree Basu: University of Minnesota
Jenny C. Taylor: University of Oxford
Alistair T. Pagnamenta: University of Oxford
Helene Dreau: University of Oxford
Jude Craft: Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust
Elizabeth Ormondroyd: University of Oxford
Hugh Watkins: University of Oxford
Eric A. Hendrickson: University of Minnesota
Emily M. Mace: Columbia University
Jordan S. Orange: Columbia University
Hideki Aihara: University of Minnesota
Grant S. Stewart: University of Birmingham
Edward Blair: Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust
Jeanette Gowen Cook: University of North Carolina
Anja-Katrin Bielinsky: University of Minnesota

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21878-x

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