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; Anja Katrin Bielinsky

doi:10.1038/s41467-021-21878-x

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. MaceJordan S. Orange, Hideki Aihara, Grant S. Stewart, Edward Blair, Jeanette Gowen Cook, Anja Katrin Bielinsky

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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.

Original language	English (US)
Article number	1626
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21878-x
State	Published - Dec 1 2021

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© 2021, The Author(s).

PubMed: MeSH publication types

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Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

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Baxley, R. M., Leung, W., Schmit, M. M., Matson, J. P., Yin, L., Oram, M. K., Wang, L., Taylor, J., Hedberg, J., Rogers, C. B., Harvey, A. J., Basu, D., Taylor, J. C., Pagnamenta, A. T., Dreau, H., Craft, J., Ormondroyd, E., Watkins, H., Hendrickson, E. A., ... Bielinsky, A. K. (2021). Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening. Nature communications, 12(1), Article 1626. https://doi.org/10.1038/s41467-021-21878-x

Baxley, RM, Leung, W, Schmit, MM, Matson, JP, Yin, L, Oram, MK, Wang, L, Taylor, J, Hedberg, J, Rogers, CB, Harvey, AJ, Basu, D, Taylor, JC, Pagnamenta, AT, Dreau, H, Craft, J, Ormondroyd, E, Watkins, H, Hendrickson, EA, Mace, EM, Orange, JS, Aihara, H, Stewart, GS, Blair, E, Cook, JG & Bielinsky, AK 2021, 'Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening', Nature communications, vol. 12, no. 1, 1626. https://doi.org/10.1038/s41467-021-21878-x

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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.",

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

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AU - Matson, Jacob Peter

AU - Yin, Lulu

AU - Oram, Marissa K.

AU - Wang, Liangjun

AU - Taylor, John

AU - Hedberg, Jack

AU - Rogers, Colette B.

AU - Harvey, Adam J.

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AU - Taylor, Jenny C.

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AU - Dreau, Helene

AU - Craft, Jude

AU - Ormondroyd, Elizabeth

AU - Watkins, Hugh

AU - Hendrickson, Eric A.

AU - Mace, Emily M.

AU - Orange, Jordan S.

AU - Aihara, Hideki

AU - Stewart, Grant S.

AU - Blair, Edward

AU - Cook, Jeanette Gowen

AU - Bielinsky, Anja Katrin

PY - 2021/12/1

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N2 - 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.

AB - 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.

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

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

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