title: dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure.
abstract: We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of thisDUTmutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance.
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Reinaldo Sousa
authors.initials: RS
authors.lastname: Dos Santos
authors.affiliation: INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Daures
authors.affiliation: INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Philippi
authors.affiliation: INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Romero
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy.
authors.forename: Lorella
authors.identifier: 0000-0002-6698-2962
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Senée
authors.affiliation: Centre National de Génotypage, Institut de Génomique, Commissariat à l'Energie Atomique, Evry, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bacq
authors.affiliation: Centre National de Génotypage, Institut de Génomique, Commissariat à l'Energie Atomique, Evry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Besse
authors.affiliation: Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Department of Diabetes and Endocrinology, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Baz
authors.initials: B
authors.lastname: Baz
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Laura
authors.identifier: 0000-0003-2931-9317
authors.initials: L
authors.lastname: Marroquí
authors.affiliation: Aplastic Anemia Reference Centre, Hematology Laboratory, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, INSERM U944, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ivanoff
authors.affiliation: Aplastic Anemia Reference Centre, Hematology Laboratory, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, INSERM U944, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Masliah-Planchon
authors.affiliation: Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Université Lyon 1, Lyon, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.affiliation: Aplastic Anemia Reference Centre, Hematology Laboratory, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, INSERM U944, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Hematology Transplantation, Department of Hematology, Immunology and Oncology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Decio L
authors.identifier: 0000-0003-2453-5889
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Department of Diabetes and Endocrinology, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.affiliation: INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France cecile.julier@inserm.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Julier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D001855:Bone Marrow Diseases / Q000235:genetics*; D000080983:Bone Marrow Failure Disorders; D002648:Child; D003241:Consanguinity; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009154:Mutation; D011755:Pyrophosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D017422:Sequence Analysis, DNA; D013577:Syndrome; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase