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 / Description of output

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	6664
Pages (from-to)	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

Keywords / Materials (for Non-textual outputs)

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: Creative Commons: Attribution (CC-BY)

Grange et al_full paper_AcceptedManuscriptAccepted author manuscript, 6.49 MBLicence: Creative Commons: Attribution (CC-BY)
OA_Pathogenic variants in SLF2 and SMC5Final published version, 3.46 MBLicence: Creative Commons: Attribution (CC-BY)

Cite this

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), 6664. Article 6664. https://doi.org/10.1038/s41467-022-34349-8

@article{26425d696fcc49a085a8abfcc95e3b8f,

title = "Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy",

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 = "Funding Information: We would like to thank the parents and affected individuals from the Atel{\'i}s Syndrome families for taking part in this study and generously donating tissue samples. We would also like to thank Agata Smorgorzewska, Kasper Fugger and Stephen West for providing plasmids expressing RusA, Gen1, Mus81 and Eme1. G.S.S., R.H., G.S.M., S.L.C., A.G. are funded by a CR-UK Program Grant (C17183/A23303). L.J.G. is supported by a joint funded University of Birmingham and CR-UK Ph.D studentship (C17422/A25154). J.J.R. and A.M.R.T. are supported by the University of Birmingham. S.S.J. is supported by a project grant funded by the Great Ormond Street Hospital Charity and Sparks (V5019). R.F.S. and N.Mai are supported by Novo Nordisk Foundation (NNF14CC0001) and Independent Research Fund Denmark (9040-00038B). D.P. and A.P.J. are supported by a European Union Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant (grant agreement 788093) and by a Medical Research Council (MRC) Unit core grant (U127580972). N.Mat is supported by AMED (JP21ek0109486, JP21ek0109549, and JP21ek0109493). Y.U. is supported by JSPS KAKENHI (JP21K15907). A.K.B. and R.M.B. are supported by grants from the National Institutes of Health (R01 GM134681 and R35 GM141805). F.U. is funded by the Higher Education Commission of Pakistan under the International research support initiative program (IRSIP). E.E.D. is supported by US National Institutes of Health grant R01 MH106826 and is the Ann Marie and Francis Klocke MD Research Scholar. Funding Information: We would like to thank the parents and affected individuals from the Atel{\'i}s Syndrome families for taking part in this study and generously donating tissue samples. We would also like to thank Agata Smorgorzewska, Kasper Fugger and Stephen West for providing plasmids expressing RusA, Gen1, Mus81 and Eme1. G.S.S., R.H., G.S.M., S.L.C., A.G. are funded by a CR-UK Program Grant (C17183/A23303). L.J.G. is supported by a joint funded University of Birmingham and CR-UK Ph.D studentship (C17422/A25154). J.J.R. and A.M.R.T. are supported by the University of Birmingham. S.S.J. is supported by a project grant funded by the Great Ormond Street Hospital Charity and Sparks (V5019). R.F.S. and N.Mai are supported by Novo Nordisk Foundation (NNF14CC0001) and Independent Research Fund Denmark (9040-00038B). D.P. and A.P.J. are supported by a European Union Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant (grant agreement 788093) and by a Medical Research Council (MRC) Unit core grant (U127580972). N.Mat is supported by AMED (JP21ek0109486, JP21ek0109549, and JP21ek0109493). Y.U. is supported by JSPS KAKENHI (JP21K15907). A.K.B. and R.M.B. are supported by grants from the National Institutes of Health (R01 GM134681 and R35 GM141805). F.U. is funded by the Higher Education Commission of Pakistan under the International research support initiative program (IRSIP). E.E.D. is supported by US National Institutes of Health grant R01 MH106826 and is the Ann Marie and Francis Klocke MD Research Scholar. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

day = "4",

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

language = "English",

volume = "13",

pages = "6664",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, 6664, pp. 6664. 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 - Funding Information: We would like to thank the parents and affected individuals from the Atelís Syndrome families for taking part in this study and generously donating tissue samples. We would also like to thank Agata Smorgorzewska, Kasper Fugger and Stephen West for providing plasmids expressing RusA, Gen1, Mus81 and Eme1. G.S.S., R.H., G.S.M., S.L.C., A.G. are funded by a CR-UK Program Grant (C17183/A23303). L.J.G. is supported by a joint funded University of Birmingham and CR-UK Ph.D studentship (C17422/A25154). J.J.R. and A.M.R.T. are supported by the University of Birmingham. S.S.J. is supported by a project grant funded by the Great Ormond Street Hospital Charity and Sparks (V5019). R.F.S. and N.Mai are supported by Novo Nordisk Foundation (NNF14CC0001) and Independent Research Fund Denmark (9040-00038B). D.P. and A.P.J. are supported by a European Union Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant (grant agreement 788093) and by a Medical Research Council (MRC) Unit core grant (U127580972). N.Mat is supported by AMED (JP21ek0109486, JP21ek0109549, and JP21ek0109493). Y.U. is supported by JSPS KAKENHI (JP21K15907). A.K.B. and R.M.B. are supported by grants from the National Institutes of Health (R01 GM134681 and R35 GM141805). F.U. is funded by the Higher Education Commission of Pakistan under the International research support initiative program (IRSIP). E.E.D. is supported by US National Institutes of Health grant R01 MH106826 and is the Ann Marie and Francis Klocke MD Research Scholar. Funding Information: We would like to thank the parents and affected individuals from the Atelís Syndrome families for taking part in this study and generously donating tissue samples. We would also like to thank Agata Smorgorzewska, Kasper Fugger and Stephen West for providing plasmids expressing RusA, Gen1, Mus81 and Eme1. G.S.S., R.H., G.S.M., S.L.C., A.G. are funded by a CR-UK Program Grant (C17183/A23303). L.J.G. is supported by a joint funded University of Birmingham and CR-UK Ph.D studentship (C17422/A25154). J.J.R. and A.M.R.T. are supported by the University of Birmingham. S.S.J. is supported by a project grant funded by the Great Ormond Street Hospital Charity and Sparks (V5019). R.F.S. and N.Mai are supported by Novo Nordisk Foundation (NNF14CC0001) and Independent Research Fund Denmark (9040-00038B). D.P. and A.P.J. are supported by a European Union Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant (grant agreement 788093) and by a Medical Research Council (MRC) Unit core grant (U127580972). N.Mat is supported by AMED (JP21ek0109486, JP21ek0109549, and JP21ek0109493). Y.U. is supported by JSPS KAKENHI (JP21K15907). A.K.B. and R.M.B. are supported by grants from the National Institutes of Health (R01 GM134681 and R35 GM141805). F.U. is funded by the Higher Education Commission of Pakistan under the International research support initiative program (IRSIP). E.E.D. is supported by US National Institutes of Health grant R01 MH106826 and is the Ann Marie and Francis Klocke MD Research Scholar. Publisher Copyright: © 2022, The Author(s).

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

U2 - 10.1038/s41467-022-34349-8

DO - 10.1038/s41467-022-34349-8

M3 - Article

C2 - 36333305

SN - 2041-1723

VL - 13

SP - 6664

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6664

ER -

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

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