Journal
DIABETES
Volume 66, Issue 4, Pages 1086-1096Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db16-0839
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Funding
- Agence Nationale de la Recherche [ANR-09-GENO-021]
- European Foundation for the Study of Diabetes/JDRF/ Novo Nordisk
- Assistance Publique-Hopitaux de Paris (Programme Hospitalier de Recherche Clinique DIAGENE)
- GIS Maladies Rares
- France Genomique (DIAPED)
- European Union Framework Programme Horizon (project T2DSystems)
- Fonds National de la Recherche Scientifique, Belgium
- Actions de Recherche Concertee de la Communaute Francaise, Belgium
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil
- Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, France
- Fonds National de la Recherche, Belgium
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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 beta-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for beta-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance.
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