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

• DOI: 10.2337/db16-0839
• Publication Date: 2017-01-11T02:20:24Z
• Authors: Reinaldo Sousa Do...; Mathilde Daures; Anne Philippi; Sophie Romero; Lorella Marselli; Piero Marchetti; Valérie Senée; Delphine Bacq; Céline Besse; Baz Baz; Laura Marroquí; Sarah Ivanoff; Julien Masliah-Pl...; Marc Nicolino; Jean Soulier; Gérard Socié; Decio L. Eizirik; Jean-François Gau...; Cécile Julier
• Keywords: Bone marrow failure

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 remotely consanguineous patient from family two affected siblings, we identified single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located dUTPase (DUT) gene (National Center for Biotechnology Information Gene ID 1854), both mitochondrial (DUT-M p.Y142C) and nuclear (DUT-N p.Y54C) isoforms. found same an unrelated aplasia whereas none of >60,000 subjects Exome Aggregation Consortium (ExAC) was this mutation. This replicated observation probability highly significant, thus confirming role DUT syndrome. is key enzyme maintaining DNA integrity preventing misincorporation uracil into DNA, which results toxicity cell death. showed that silencing human rat pancreatic β-cells apoptosis via intrinsic death pathway. Our findings support importance tight control metabolism β-cell warrant close metabolic monitoring patients treated drugs dUTP balance.