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Diabetes. 2017 Apr;66(4):1086-1096. doi: 10.2337/db16-0839. Epub 2017 Jan 10.

dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure.

Author information

1
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
2
INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
3
Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy.
4
Centre National de Génotypage, Institut de Génomique, Commissariat à l'Energie Atomique, Evry, France.
5
Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Department of Diabetes and Endocrinology, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
6
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.
7
Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Université Lyon 1, Lyon, France.
8
Hematology Transplantation, Department of Hematology, Immunology and Oncology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
9
INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France cecile.julier@inserm.fr.

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 this DUT mutation 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.

PMID:
28073829
DOI:
10.2337/db16-0839
[Indexed for MEDLINE]
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