Publication Details

Title :

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism


Nature Genetics

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John J Reynolds,
Louise S Bicknell,
Paula Carroll,
Martin R Higgs,
Ranad Shaheen,
Jennie E Murray,
Dimitrios K Papadopoulos,
Andrea Leitch,
Olga Murina,
Žygimantė Tarnauskaitė,
Sarah R Wessel,
Anastasia Zlatanou,
Audrey Vernet,
Alex von Kriegsheim,
Rachel M A Mottram,
Clare V Logan,
Hannah Bye,
Yun Li,
Alexander Brean,
Sateesh Maddirevula,
Rachel C Challis,
Kassiani Skouloudaki,
Agaadir Almoisheer,
Hessa S Alsaif,
Ariella Amar,
Natalie J Prescott,
Michael B Bober,
Angela Duker,
Eissa Faqeih,
Mohammed Zain Seidahmed,
Saeed Al Tala,
Abdulrahman Alswaid,
Saleem Ahmed,
Jumana Yousuf Al-Aama,
Janine Altmüller,
Mohammed Al Balwi,
Angela F Brady,
Luciana Chessa,
Helen Cox,
Rita Fischetto,
Raoul Heller,
Bertram D Henderson,
Emma Hobson,
Peter Nürnberg,
E Ferda Percin,
Angela Peron,
Luigina Spaccini,
Alan J Quigley,
Seema Thakur,
Carol A Wise,
Grace Yoon,
Maha Alnemer,
Pavel Tomancak,
Gökhan Yigit,
A Malcolm R Taylor,
Martin A M Reijns,
Michael A Simpson,
David Cortez,
Fowzan S Alkuraya,
Christopher G Mathew,
Andrew P Jackson
& Grant S Stewart


Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

John J Reynolds,
Martin R Higgs,
Anastasia Zlatanou,
Audrey Vernet,
Rachel M A Mottram,
Alexander Brean,
A Malcolm R Taylor &
Grant S Stewart

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Louise S Bicknell,
Paula Carroll,
Jennie E Murray,
Andrea Leitch,
Olga Murina,
Alex von Kriegsheim,
Clare V Logan,
Rachel C Challis,
Martin A M Reijns &
Andrew P Jackson

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Ranad Shaheen,
Sateesh Maddirevula,
Agaadir Almoisheer,
Hessa S Alsaif &
Fowzan S Alkuraya

Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Dimitrios K Papadopoulos,
Kassiani Skouloudaki &
Pavel Tomancak

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Sarah R Wessel &
David Cortez

Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King’s College London, Guy’s Hospital, London, UK.

Hannah Bye,
Ariella Amar,
Natalie J Prescott,
Michael A Simpson &
Christopher G Mathew

Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.

Yun Li &
Gökhan Yigit

Nemours–Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.

Michael B Bober &
Angela Duker

Department of Pediatric Subspecialties, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.

Eissa Faqeih

Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.

Mohammed Zain Seidahmed

Armed Forces Hospital, SR. P.D. Genetic Unit. Khamis Mushayt, Saudi Arabia.

Saeed Al Tala

Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

Abdulrahman Alswaid

Department of Genetic Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

Saleem Ahmed &
Jumana Yousuf Al-Aama

Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.

Saleem Ahmed &
Jumana Yousuf Al-Aama

Cologne Center for Genomics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

Janine Altmüller &
Peter Nürnberg

Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia.

Mohammed Al Balwi

North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.

Angela F Brady

Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy.

Luciana Chessa

West Midlands Regional Clinical Genetics Service, Birmingham Women’s Hospital, West Midlands, UK.

Helen Cox

Pediatric Hospital Giovanni XXIII, Bari, Italy.

Rita Fischetto

Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.

Raoul Heller

Divison of Clinical Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.

Bertram D Henderson

Department of Genetics, Yorkshire Regional Genetic service, Chapel Allerton Hospital, Leeds, UK.

Emma Hobson

Department of Medical Genetics, Gazi University Faculty of Medicine, Besevler Ankara, Turkey.

E Ferda Percin

Clinical Genetics Unit, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, V. Buzzi Children’s Hospital, Universita’ degli Studi di Milano, Milan, Italy.
Angela Peron &
Luigina Spaccini

Child Neuropsychiatry Unit–Epilepsy Center, San Paolo University Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Angela Peron

Dept of Radiology, Royal Hospital for Sick Children, Edinburgh, UK.

Alan J Quigley

Department of Genetic and Fetal Medicine, Fortis Lafemme, New Delhi, India.

Seema Thakur

Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.

Carol A Wise

Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, Canada.

Grace Yoon

Department of Pediatrics, Division of Neurology, Hospital for Sick Children, University of Toronto, Toronto, Canada.

Grace Yoon

Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Maha Alnemer

Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Christopher G Mathew

Year of Publication:


ISSN Number:





To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.