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

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Access

10.1038/s41467-021-21878-x

OpenUrl availability

Full text

Cite this

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

@article{1c8cf63362e54011ad56106c3d2491d7,

title = "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening",

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}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-21878-x",

language = "English (US)",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

AU - Baxley, Ryan M.

AU - Leung, Wendy

AU - Schmit, Megan M.

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.

AU - Basu, Debashree

AU - Taylor, Jenny C.

AU - Pagnamenta, Alistair T.

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

Y1 - 2021/12/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85102519314&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85102519314&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-21878-x

DO - 10.1038/s41467-021-21878-x

M3 - Article

C2 - 33712616

AN - SCOPUS:85102519314

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1626

ER -

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

Abstract

Bibliographical note

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this