Primary Microcephaly, Impaired DNA Replication, and Genomic Instability Caused by Compound Heterozygous ATR Mutations

Authors

  • Houda Mokrani-Benhelli,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
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    • Authors Houda Mokrani-Benhelli and Laetitia Gaillard equally contributed to this work.

  • Laetitia Gaillard,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
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    • Authors Houda Mokrani-Benhelli and Laetitia Gaillard equally contributed to this work.

  • Patricia Biasutto,

    1. Genomic Vision, Paris Santé Cochin, Paris, France
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  • Tangui Le Guen,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
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  • Fabien Touzot,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    3. AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France
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  • Nadia Vasquez,

    1. AP-HP Hematology Laboratory, Hôpital Saint-Louis, Paris, France
    2. INSERM U728 and UMR944, Hôpital Saint-Louis, Paris, France
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  • Jun Komatsu,

    1. Genomic Vision, Paris Santé Cochin, Paris, France
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  • Emmanuel Conseiller,

    1. Genomic Vision, Paris Santé Cochin, Paris, France
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  • Capucine Pïcard,

    1. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    2. AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France
    3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Paris, France
    4. Study Center of Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France
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  • Eliane Gluckman,

    1. Professor Emeritus, University Paris VII, Hôpital Saint-Louis, Paris, France
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  • Christine Francannet,

    1. Centre Hospitalier Universitaire Hôtel Dieu, Clermont-Ferrand, France
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  • Alain Fischer,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    3. AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France
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  • Anne Durandy,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    3. AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France
    4. Study Center of Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France
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  • Jean Soulier,

    1. AP-HP Hematology Laboratory, Hôpital Saint-Louis, Paris, France
    2. INSERM U728 and UMR944, Hôpital Saint-Louis, Paris, France
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  • Jean-Pierre de Villartay,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    3. AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France
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  • Marina Cavazzana-Calvo,

    1. Genome Dynamics in the Immune System, INSERM, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    3. AP-HP, Hôpital Necker Enfants-Malades, Département de Biothérapie, Paris, France
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  • Patrick Revy

    Corresponding author
    1. Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France
    • Genome Dynamics in the Immune System, INSERM, Paris, France
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  • Communicated by Stylianos E. Antonarakis

  • Contract grant sponsors: Institut National de la Santé et de la Recherche Médicale; Institut National du Cancer (INCa)/Cancéropôle Ile de France; Ligue National contre le Cancer (Equipe labellisée La Ligue); Fondation Imagine.

Correspondence to: Patrick Revy, Inserm U768, 149 rue de Sèvres, 75015 Paris, France. E-mail: patrick.revy@inserm.fr

ABSTRACT

Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity.

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