Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

Davor Lessel; Bruno Vaz; Swagata Halder; Paul J. Lockhart; Ivana Marinovic-Terzic; Jaime Lopez-Mosqueda; Melanie Philipp; Joe C.H. Sim; Katherine R. Smith; Judith Oehler; Elisa Cabrera; Raimundo Freire; Kate Pope; Amsha Nahid; Fiona Norris; Richard J. Leventer; Martin B. Delatycki; Gotthold Barbi; Simon Von Ameln; Josef Högel; Marina Degoricija; Regina Fertig; Martin D. Burkhalter; Kay Hofmann; Holger Thiele; Janine Altmüller; Gudrun Nürnberg; Peter Nürnberg; Melanie Bahlo; George M. Martin; Cora M. Aalfs; Junko Oshima; Janos Terzic; David J. Amor; Ivan Dikic; Kristijan Ramadan; Christian Kubisch

doi:10.1038/ng.3103

Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

Davor Lessel, Bruno Vaz, Swagata Halder, Paul J. Lockhart, Ivana Marinovic-Terzic, Jaime Lopez-Mosqueda, Melanie Philipp, Joe C.H. Sim, Katherine R. Smith, Judith Oehler, Elisa Cabrera, Raimundo Freire, Kate Pope, Amsha Nahid, Fiona Norris, Richard J. Leventer, Martin B. Delatycki, Gotthold Barbi, Simon Von Ameln, Josef HögelMarina Degoricija, Regina Fertig, Martin D. Burkhalter, Kay Hofmann, Holger Thiele, Janine Altmüller, Gudrun Nürnberg, Peter Nürnberg, Melanie Bahlo, George M. Martin, Cora M. Aalfs, Junko Oshima, Janos Terzic, David J. Amor, Ivan Dikic, Kristijan Ramadan, Christian Kubisch^*

^*Corresponding author for this work

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

167 Citations (Scopus)

Abstract

Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

Original language	English
Pages (from-to)	1239-1244
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	11
DOIs	https://doi.org/10.1038/ng.3103
Publication status	Published - Nov 5 2014
Externally published	Yes

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© 2014 Nature America, Inc. All rights reserved.

ASJC Scopus Subject Areas

Genetics

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Lessel, D., Vaz, B., Halder, S., Lockhart, P. J., Marinovic-Terzic, I., Lopez-Mosqueda, J., Philipp, M., Sim, J. C. H., Smith, K. R., Oehler, J., Cabrera, E., Freire, R., Pope, K., Nahid, A., Norris, F., Leventer, R. J., Delatycki, M. B., Barbi, G., Von Ameln, S., ... Kubisch, C. (2014). Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nature Genetics, 46(11), 1239-1244. https://doi.org/10.1038/ng.3103

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title = "Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features",

abstract = "Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.",

author = "Davor Lessel and Bruno Vaz and Swagata Halder and Lockhart, {Paul J.} and Ivana Marinovic-Terzic and Jaime Lopez-Mosqueda and Melanie Philipp and Sim, {Joe C.H.} and Smith, {Katherine R.} and Judith Oehler and Elisa Cabrera and Raimundo Freire and Kate Pope and Amsha Nahid and Fiona Norris and Leventer, {Richard J.} and Delatycki, {Martin B.} and Gotthold Barbi and {Von Ameln}, Simon and Josef H{\"o}gel and Marina Degoricija and Regina Fertig and Burkhalter, {Martin D.} and Kay Hofmann and Holger Thiele and Janine Altm{\"u}ller and Gudrun N{\"u}rnberg and Peter N{\"u}rnberg and Melanie Bahlo and Martin, {George M.} and Aalfs, {Cora M.} and Junko Oshima and Janos Terzic and Amor, {David J.} and Ivan Dikic and Kristijan Ramadan and Christian Kubisch",

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Lessel, D, Vaz, B, Halder, S, Lockhart, PJ, Marinovic-Terzic, I, Lopez-Mosqueda, J, Philipp, M, Sim, JCH, Smith, KR, Oehler, J, Cabrera, E, Freire, R, Pope, K, Nahid, A, Norris, F, Leventer, RJ, Delatycki, MB, Barbi, G, Von Ameln, S, Högel, J, Degoricija, M, Fertig, R, Burkhalter, MD, Hofmann, K, Thiele, H, Altmüller, J, Nürnberg, G, Nürnberg, P, Bahlo, M, Martin, GM, Aalfs, CM, Oshima, J, Terzic, J, Amor, DJ, Dikic, I, Ramadan, K & Kubisch, C 2014, 'Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features', Nature Genetics, vol. 46, no. 11, pp. 1239-1244. https://doi.org/10.1038/ng.3103

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AU - Lessel, Davor

AU - Vaz, Bruno

AU - Halder, Swagata

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AU - Marinovic-Terzic, Ivana

AU - Lopez-Mosqueda, Jaime

AU - Philipp, Melanie

AU - Sim, Joe C.H.

AU - Smith, Katherine R.

AU - Oehler, Judith

AU - Cabrera, Elisa

AU - Freire, Raimundo

AU - Pope, Kate

AU - Nahid, Amsha

AU - Norris, Fiona

AU - Leventer, Richard J.

AU - Delatycki, Martin B.

AU - Barbi, Gotthold

AU - Von Ameln, Simon

AU - Högel, Josef

AU - Degoricija, Marina

AU - Fertig, Regina

AU - Burkhalter, Martin D.

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AU - Altmüller, Janine

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AU - Martin, George M.

AU - Aalfs, Cora M.

AU - Oshima, Junko

AU - Terzic, Janos

AU - Amor, David J.

AU - Dikic, Ivan

AU - Ramadan, Kristijan

AU - Kubisch, Christian

PY - 2014/11/5

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N2 - Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

AB - Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

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Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

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