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 () 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.

Structural Insight into African Swine Fever Virus dUTPase Reveals a Novel Folding Pattern in the dUTPase Family

“…Previous studies have shown that dUTPase regulation plays a vital role in programmed cell death in Drosophila, yeast and mammalian cells (29,30). Furthermore, a dysfunctional dUTPase causes a novel monogenic syndrome that leads to diabetes and bone marrow failure (31). Similarly, the dUTPases of many viruses, including poxviruses, herpesviruses, and several vertebrate retroviruses, play important roles in efficient virus replication; therefore, mutations in the dUTPase sequence can significantly affect the biological and pathogenic properties of these viruses (32)(33)(34)(35)(36).…”

Redox status of cysteines does not alter functional properties of human dUTPase but the Y54C mutation involved in monogenic diabetes decreases protein stability

“…It has also been shown that dUTPase overexpression in cancers decrease the effectivity of thymidylate-synthase targeted chemotherapy (e. g. 5-fluorouracil, methotrexate) 54 – 57 and is involved in development of resistance against the treatment 58 , 59 . Interestingly, a human dUTPase mutation (Tyr54Cys) located outside the conserved region was suggested to be responsible for monogenic syndrome associated with diabetes type 2 and bone marrow failure 53 . This report was the first and to date the only case where a dUTPase mutation has been associated with human disease.…”

Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update

“…Although the supportive evidence presented in this study is overwhelmingly genetic in nature, we also share experimental evidence in support of the pathogenesis of the missense variant identified in DUT. Since the case reported by Dos Santos et al (2017), no follow up studies have been published on the involvement of DUT in the pathogenesis of the syndrome of diabetes with bone marrow failure. Without functional validation, the novel missense variant we encountered in a patient with that syndrome will not have much weight due to lack of compelling segregation.…”