title: A nonsense mutation in the DNA repair factor Hebo causes mild bone marrow failure and microcephaly.
abstract: Inherited bone marrow failure syndromes are human conditions in which one or several cell lineages of the hemopoietic system are affected. They are present at birth or may develop progressively. They are sometimes accompanied by other developmental anomalies. Three main molecular causes have been recognized to result in bone marrow failure syndromes: (1) defects in the Fanconi anemia (FA)/BRCA DNA repair pathway, (2) defects in telomere maintenance, and (3) abnormal ribosome biogenesis. We analyzed a patient with mild bone marrow failure and microcephaly who did not present with the typical FA phenotype. Cells from this patient showed increased sensitivity to ionizing radiations and phleomycin, attesting to a probable DNA double strand break (dsb) repair defect. Linkage analysis and whole exome sequencing revealed a homozygous nonsense mutation in the ERCC6L2 gene. We identified a new ERCC6L2 alternative transcript encoding the DNA repair factor Hebo, which is critical for complementation of the patient's DNAdsb repair defect. Sequence analysis revealed three structured regions within Hebo: a TUDOR domain, an adenosine triphosphatase domain, and a new domain, HEBO, specifically present in Hebo direct orthologues. Hebo is ubiquitously expressed, localized in the nucleus, and rapidly recruited to DNAdsb's in an NBS1-dependent manner.
authors.affiliation: Genome Dynamics in the Immune System Laboratory, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institut d'Hématologie et d'Oncologie Pédiatrique, 69008 Lyon, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Pondarre
authors.affiliation: Commisariat à l'Energie Atomique, Division des Sciences du Vivant, Institut National de la Santé et de la Recherche Médicale, UMR 967 CEA, Université Paris Diderot, 75013 Paris, France Institut de Radiobiologie Cellulaire et Moléculaire Fontenay-aux-Roses, Université Paris Sud, 91400 Orsay, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Pennarun
authors.affiliation: Service d'Hématologie, Groupement Hospitalier Lyon Sud, Hospices Civils de Lyon, 69002 Lyon, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Labussiere-Wallet
authors.affiliation: Genome Dynamics in the Immune System Laboratory, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Vera
authors.affiliation: Genome Dynamics in the Immune System Laboratory, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: France
authors.affiliation: Genome Dynamics in the Immune System Laboratory, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Chansel
authors.affiliation: Biotechnology Department, Hospices Civils de Lyon, 69002 Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouvet
authors.affiliation: Genome Dynamics in the Immune System Laboratory, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.affiliation: Institut de Cancérologie Gustave Roussy, Centre National de la Recherche Scientifique, UMR 8200, Université Paris Sud, 91400 Orsay, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lopez
authors.affiliation: Institute of Hematology, Institut National de la Santé et de la Recherche Médicale, UMR 944, Centre National de la Recherche Scientifique, UMR 7212, Saint-Louis Hospital and Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Commisariat à l'Energie Atomique, Division des Sciences du Vivant, Institut National de la Santé et de la Recherche Médicale, UMR 967 CEA, Université Paris Diderot, 75013 Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7590, Université Pierre et Marie Curie, Museum National d'Histoire Naturelle, Institut de recherche pour le développement, Institut Universitaire de Cancérologie, Sorbonne Universités, 75005 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.affiliation: Genome Dynamics in the Immune System Laboratory, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France devillartay@gmail.com.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
mesh_terms: D000293:Adolescent; D001855:Bone Marrow Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018389:Codon, Nonsense; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; C112156:NBN protein, human; D009687:Nuclear Proteins; D004265:DNA Helicases; C587425:ERCC6L2 protein, human