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

Author

Listed:
  • 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
    Oxford NIHR Biomedical Research Centre)

  • Alistair T. Pagnamenta

    (University of Oxford
    Oxford NIHR Biomedical Research Centre)

  • 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)

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.

Suggested Citation

  • 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 & Je, 2021. "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21878-x
    DOI: 10.1038/s41467-021-21878-x
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    Cited by:

    1. Chiara Masnovo & Zohar Paleiov & Daniel Dovrat & Laurel K. Baxter & Sofia Movafaghi & Amir Aharoni & Sergei M. Mirkin, 2024. "Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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