Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Laura J Grange; John J Reynolds; Farid Ullah; Bertrand Isidor; Robert F Shearer; Xenia Latypova; Ryan M Baxley; Antony W Oliver; Anil Ganesh; Sophie L Cooke; Satpal S Jhujh; Gavin S McNee; Robert Hollingworth; Martin R Higgs; Toyoaki Natsume; Tahir Khan; Gabriel Á. Martos-Moreno; Sharon Chupp; Christopher G. Mathew; David Parry; Michael A. Simpson; Nahid Nahavandi; Zafer Yüksel; Mojgan Drasdo; Anja Kron; Petra Vogt; Annemarie Jonasson; Saad Ahmed Seth; Claudia Gonzaga-Jauregui; Karlla W Brigatti; Alexander P A Stegmann; Masato Kanemaki; Dragana Josifova; Yuri Uchiyama; Yukiko Oh; Akira Morimoto; Hitoshi Osaka; Zineb Ammous; Jesús Argente; Naomichi Matsumoto; Constance T.R.M. Stumpel; Alexander M.R. Taylor; Andrew P. Jackson; Anja-Katrin Bielinsky; Niels Mailand; Cedric Le Caignec; Erica E. Davis; Grant S. Stewart

doi:10.1038/s41467-022-34349-8

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Laura J Grange, John J Reynolds, Farid Ullah, Bertrand Isidor, Robert F Shearer, Xenia Latypova, Ryan M Baxley, Antony W Oliver, Anil Ganesh, Sophie L Cooke, Satpal S Jhujh, Gavin S McNee, Robert Hollingworth, Martin R Higgs, Toyoaki Natsume, Tahir Khan, Gabriel Á. Martos-Moreno, Sharon Chupp, Christopher G. Mathew, David ParryMichael A. Simpson, Nahid Nahavandi, Zafer Yüksel, Mojgan Drasdo, Anja Kron, Petra Vogt, Annemarie Jonasson, Saad Ahmed Seth, Claudia Gonzaga-Jauregui, Karlla W Brigatti, Alexander P A Stegmann, Masato Kanemaki, Dragana Josifova, Yuri Uchiyama, Yukiko Oh, Akira Morimoto, Hitoshi Osaka, Zineb Ammous, Jesús Argente, Naomichi Matsumoto, Constance T.R.M. Stumpel, Alexander M.R. Taylor, Andrew P. Jackson, Anja-Katrin Bielinsky, Niels Mailand, Cedric Le Caignec, Erica E. Davis, Grant S. Stewart

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

Abstract

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

Original language	English
Article number	22
Number of pages	6664
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34349-8
Publication status	Published - 4 Nov 2022

Bibliographical note

Copyright © The Author(s), 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

Keywords

Humans
Cell Cycle Proteins/genetics
Microcephaly/genetics
DNA Repair/genetics
Chromosomes/metabolism
Genomic Instability
DNA-Binding Proteins/metabolism
Ubiquitin-Protein Ligases/metabolism
Chromosomal Proteins, Non-Histone/metabolism

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10.1038/s41467-022-34349-8Licence: CC BY 4.0

L J Grange J J Reynolds et al_Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
Copyright © The Author(s), 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
Final published version, 3.46 MBLicence: CC BY 4.0

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Grange, L. J., Reynolds, J. J., Ullah, F., Isidor, B., Shearer, R. F., Latypova, X., Baxley, R. M., Oliver, A. W., Ganesh, A., Cooke, S. L., Jhujh, S. S., McNee, G. S., Hollingworth, R., Higgs, M. R., Natsume, T., Khan, T., Martos-Moreno, G. Á., Chupp, S., Mathew, C. G., ... Stewart, G. S. (2022). Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Communications, 13(1), Article 22. https://doi.org/10.1038/s41467-022-34349-8

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abstract = "Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atel{\'i}s (meaning - incomplete) Syndrome. Analysis of Atel{\'i}s Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.",

keywords = "Humans, Cell Cycle Proteins/genetics, Microcephaly/genetics, DNA Repair/genetics, Chromosomes/metabolism, Genomic Instability, DNA-Binding Proteins/metabolism, Ubiquitin-Protein Ligases/metabolism, Chromosomal Proteins, Non-Histone/metabolism",

author = "Grange, {Laura J} and Reynolds, {John J} and Farid Ullah and Bertrand Isidor and Shearer, {Robert F} and Xenia Latypova and Baxley, {Ryan M} and Oliver, {Antony W} and Anil Ganesh and Cooke, {Sophie L} and Jhujh, {Satpal S} and McNee, {Gavin S} and Robert Hollingworth and Higgs, {Martin R} and Toyoaki Natsume and Tahir Khan and Martos-Moreno, {Gabriel {\'A}.} and Sharon Chupp and Mathew, {Christopher G.} and David Parry and Simpson, {Michael A.} and Nahid Nahavandi and Zafer Y{\"u}ksel and Mojgan Drasdo and Anja Kron and Petra Vogt and Annemarie Jonasson and Seth, {Saad Ahmed} and Claudia Gonzaga-Jauregui and Brigatti, {Karlla W} and Stegmann, {Alexander P A} and Masato Kanemaki and Dragana Josifova and Yuri Uchiyama and Yukiko Oh and Akira Morimoto and Hitoshi Osaka and Zineb Ammous and Jes{\'u}s Argente and Naomichi Matsumoto and Stumpel, {Constance T.R.M.} and Taylor, {Alexander M.R.} and Jackson, {Andrew P.} and Anja-Katrin Bielinsky and Niels Mailand and {Le Caignec}, Cedric and Davis, {Erica E.} and Stewart, {Grant S.}",

note = "Copyright {\textcopyright} The Author(s), 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.",

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doi = "10.1038/s41467-022-34349-8",

language = "English",

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journal = "Nature Communications",

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Grange, LJ, Reynolds, JJ, Ullah, F, Isidor, B, Shearer, RF, Latypova, X, Baxley, RM, Oliver, AW, Ganesh, A, Cooke, SL, Jhujh, SS, McNee, GS, Hollingworth, R, Higgs, MR, Natsume, T, Khan, T, Martos-Moreno, GÁ, Chupp, S, Mathew, CG, Parry, D, Simpson, MA, Nahavandi, N, Yüksel, Z, Drasdo, M, Kron, A, Vogt, P, Jonasson, A, Seth, SA, Gonzaga-Jauregui, C, Brigatti, KW, Stegmann, APA, Kanemaki, M, Josifova, D, Uchiyama, Y, Oh, Y, Morimoto, A, Osaka, H, Ammous, Z, Argente, J, Matsumoto, N, Stumpel, CTRM, Taylor, AMR, Jackson, AP, Bielinsky, A-K, Mailand, N, Le Caignec, C, Davis, EE & Stewart, GS 2022, 'Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy', Nature Communications, vol. 13, no. 1, 22. https://doi.org/10.1038/s41467-022-34349-8

TY - JOUR

T1 - Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

AU - Grange, Laura J

AU - Reynolds, John J

AU - Ullah, Farid

AU - Isidor, Bertrand

AU - Shearer, Robert F

AU - Latypova, Xenia

AU - Baxley, Ryan M

AU - Oliver, Antony W

AU - Ganesh, Anil

AU - Cooke, Sophie L

AU - Jhujh, Satpal S

AU - McNee, Gavin S

AU - Hollingworth, Robert

AU - Higgs, Martin R

AU - Natsume, Toyoaki

AU - Khan, Tahir

AU - Martos-Moreno, Gabriel Á.

AU - Chupp, Sharon

AU - Mathew, Christopher G.

AU - Parry, David

AU - Simpson, Michael A.

AU - Nahavandi, Nahid

AU - Yüksel, Zafer

AU - Drasdo, Mojgan

AU - Kron, Anja

AU - Vogt, Petra

AU - Jonasson, Annemarie

AU - Seth, Saad Ahmed

AU - Gonzaga-Jauregui, Claudia

AU - Brigatti, Karlla W

AU - Stegmann, Alexander P A

AU - Kanemaki, Masato

AU - Josifova, Dragana

AU - Uchiyama, Yuri

AU - Oh, Yukiko

AU - Morimoto, Akira

AU - Osaka, Hitoshi

AU - Ammous, Zineb

AU - Argente, Jesús

AU - Matsumoto, Naomichi

AU - Stumpel, Constance T.R.M.

AU - Taylor, Alexander M.R.

AU - Jackson, Andrew P.

AU - Bielinsky, Anja-Katrin

AU - Mailand, Niels

AU - Le Caignec, Cedric

AU - Davis, Erica E.

AU - Stewart, Grant S.

N1 - Copyright © The Author(s), 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

PY - 2022/11/4

Y1 - 2022/11/4

N2 - Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

AB - Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

KW - Humans

KW - Cell Cycle Proteins/genetics

KW - Microcephaly/genetics

KW - DNA Repair/genetics

KW - Chromosomes/metabolism

KW - Genomic Instability

KW - DNA-Binding Proteins/metabolism

KW - Ubiquitin-Protein Ligases/metabolism

KW - Chromosomal Proteins, Non-Histone/metabolism

UR - https://www.nature.com/articles/s41467-022-34349-8

U2 - 10.1038/s41467-022-34349-8

DO - 10.1038/s41467-022-34349-8

M3 - Article

C2 - 36333305

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 22

ER -

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Abstract

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Keywords

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