Dos Santos Reinaldo Sousa, Daures Mathilde, Philippi Anne, Romero Sophie, Marselli Lorella, Marchetti Piero, Senée Valérie, Bacq Delphine, Besse Céline, Baz Baz, Marroquí Laura, Ivanoff Sarah, Masliah-Planchon Julien, Nicolino Marc, Soulier Jean, Socié Gérard, Eizirik Decio L, Gautier Jean-François, Julier Cécile
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France.
Diabetes. 2017 Apr;66(4):1086-1096. doi: 10.2337/db16-0839. Epub 2017 Jan 10.
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 () 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 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.
我们描述了一种新的综合征，其特征为早发性糖尿病伴骨髓衰竭，主要影响红细胞系。通过对一个有两名患病同胞的家族中一名远亲近亲婚配患者进行全外显子组测序，我们在dUTPase（）基因（国家生物技术信息中心基因ID 1854）中鉴定出一个纯合错义突变（chr15.hg19:g.48,626,619A>G），该突变影响线粒体（DUT-M p.Y142C）和细胞核（DUT-N p.Y54C）两种同工型。我们在另一个有两名患病同胞的家族中一名患糖尿病和再生障碍性贫血的非亲缘近亲婚配患者中发现了相同的纯合突变，而外显子聚合联盟（ExAC）的60000多名受试者中没有一人是该突变的纯合子。这种重复观察的概率非常显著，从而证实了该突变在这种综合征中的作用。DUT是一种关键酶，通过防止尿嘧啶错误掺入DNA来维持DNA完整性，否则会导致DNA毒性和细胞死亡。我们表明，在人和大鼠胰腺β细胞中沉默DUT会通过内在细胞死亡途径导致细胞凋亡。我们的研究结果支持了严格控制DNA代谢对β细胞完整性的重要性，并保证对使用影响dUTP平衡的药物治疗的患者进行密切的代谢监测。
