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

Ryan M. Baxley; Wendy Leung; Megan Schmit; Jacob P. 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 Marie-Pierre Dreau; Jude Craft; Elizabeth Ormondroyd; Hugh C Watkins; Eric A. Hendrickson; Emily Margaret Mace; Jordan Scott Orange; Hideki Aihara; Grant S. Stewart; Edward M. Blair; Jeanette Gowen Cook; Anja‐Katrin Bielinsky

doi:10.1038/s41467-021-21878-x

Molecular BiologyNature CommunicationsMar 12, 2021

Peer-reviewed journal article

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

Ryan M. Baxley iD, Wendy Leung, Megan Schmit iD, Jacob P. Matson iD, Lulu Yin iD, Marissa K. Oram iD, Liangjun Wang iD, John Taylor iD, Jack Hedberg iD, Colette B. Rogers iD, Adam J. Harvey, Debashree Basu iD, Jenny C. Taylor iD, Alistair T. Pagnamenta iD, Helene Marie-Pierre Dreau iD, Jude Craft, Elizabeth Ormondroyd iD, Hugh C Watkins iD, Eric A. Hendrickson iD, Emily Margaret Mace iD, Jordan Scott Orange iD, Hideki Aihara iD, Grant S. Stewart iD, Edward M. Blair, Jeanette Gowen Cook iD, Anja‐Katrin Bielinsky iD

Abstract

Minichromosome maintenance protein 10 (Mcm10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 mutations 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 mutations 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 mutations in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes in both NKD and CM patients.

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