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

• DOI: 10.1038/s41467-021-21878-x
• Publication Date: 2021-03-12T11:07:02Z
• Authors: 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. Pagna...; 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; Anja-Katrin Bieli...
• Keywords: DNA Replication; 0301 basic medicine; Minichromosome Maintenance Proteins; Science; Q; Cell Cycle Proteins; Endonucleases; Article; Cell Line; 3. Good health; DNA-Binding Proteins; Killer Cells, Natural; 03 medical and health sciences; Humans; Cardiomyopathies; Alleles; Telomere Shortening

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) hypoplasia of the spleen thymus. To understand mechanism MCM10-associated disease, modeled these human lines. causes chronic replication stress that reduces viability due to increased genomic instability telomere erosion. Our data suggest loss function constrains telomerase activity by accumulating abnormal fork structures enriched single-stranded DNA. Terminally-arrested forks MCM10-deficient cells require endonucleolytic processing MUS81, as MCM10:MUS81 double mutants display decreased accelerated shortening. We propose bi-allelic predispose specific cardiac immune lineages prematurely arrest during differentiation, causing phenotypes observed both NKD RCM patients.