De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

Dual-Specificity Phosphatase 11 Is a Prognostic Biomarker of Intrahepatic Cholangiocarcinoma

BackgroundCholangiocarcinoma (CCA), including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, is a highly aggressive malignancy originating from bile duct. The prognosis of CCA is very poor, and the biomarker study is unsatisfactory compared with other common cancers.Materials and methodsIn our study, we investigated the expression of dual-specificity phosphatase 11(DUSP11) in eight pairs of iCCAs, pCCAs, and dCCAs, and their corresponding tumor-adjacent tissues, as well as their tumor-adjacent tissues with qPCR. Moreover, we investigated the expression of DUSP11 in 174 cases of CCAs with immunohistochemistry, including 74 iCCAs, 64 pCCAs, and 36 dCCAs. We classified these patients into subsets with low and high expressions of DUSP11, and evaluated the correlations between the DUSP11 subsets and clinicopathological factors. With univariate and multivariate analyses, we assessed the correlation between DUSP11 and the overall survival (OS) rates in these CCA patients.ResultsIn all the CCA subtypes, DUSP11 was elevated in CCAs compared with their paired adjacent tissues. In iCCA, pCCA, and dCCA, the percentages of DUSP11 high expression were 44.59%, 53.85%, and 55.56%, respectively. In iCCA, high DUSP11 expression was significantly associated with an advanced T stage and a poor prognosis. However, the prognostic value of DUSP11 in pCCA and dCCA was not significant. To decrease the statistical error caused by the small sample size of the dCCA cohort, we merged pCCA and dCCA into extracellular CCA (eCCA). In the 101 cases of eCCA, DUSP11 expression was also not significantly associated with the prognosis.ConclusionsDUSP11 expression was associated with tumor infiltration and the OS rate in iCCA, but not in pCCA and dCCA. DUSP11 was an independent biomarker of iCCA indicating a poor prognosis. Our results suggested that a high expression of DUSP11 was a post-operational risk factor, and detecting DUSP11 could guide the individual treatment for patients with CCA.

Dual-Specificity Phosphatase 1 (DUSP1) Has a Central Role in Redox Homeostasis and Inflammation in the Mouse Cochlea

Stress-activated protein kinases (SAPK) are associated with sensorineural hearing loss (SNHL) of multiple etiologies. Their activity is tightly regulated by dual-specificity phosphatase 1 (DUSP1), whose loss of function leads to sustained SAPK activation. Dusp1 gene knockout in mice accelerates SNHL progression and triggers inflammation, redox imbalance and hair cell (HC) death. To better understand the link between inflammation and redox imbalance, we analyzed the cochlear transcriptome in Dusp1−/− mice. RNA sequencing analysis (GSE176114) indicated that Dusp1−/− cochleae can be defined by a distinct profile of key cellular expression programs, including genes of the inflammatory response and glutathione (GSH) metabolism. To dissociate the two components, we treated Dusp1−/− mice with N-acetylcysteine, and hearing was followed-up longitudinally by auditory brainstem response recordings. A combination of immunofluorescence, Western blotting, enzymatic activity, GSH levels measurements and RT-qPCR techniques were used. N-acetylcysteine treatment delayed the onset of SNHL and mitigated cochlear damage, with fewer TUNEL+ HC and lower numbers of spiral ganglion neurons with p-H2AX foci. N-acetylcysteine not only improved the redox balance in Dusp1−/− mice but also inhibited cytokine production and reduced macrophage recruitment. Our data point to a critical role for DUSP1 in controlling the cross-talk between oxidative stress and inflammation.