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Context: The DUOX/DUOXA systems play a key role in H 2 O 2 generation in thyroid cells, which is required for iodine organification and thyroid hormone synthesis. DUOX2/DUOXA2 defects can cause congenital hypothyroidism (CH), but it is unknown whether DUOX1/DUOXA1 mutations can also cause CH. Objective: We aimed to identify DUOX1/DUOXA1 mutations and explore their role in the development of CH by investigating their functional impacts on H 2 O 2 generation. Patients and Methods: Forty-three children with CH with goiter were enrolled, in whom all exons and flanking intronic regions of DUOX1/DUOXA1 were directly sequenced. We characterized the functional effects of identified mutations on the expression of DUOX1 and DUOXA1 and H 2 O 2 generation. Results: We identified a heterozygous DUOX1 missense mutation (G > A base substitution at nucleotide 3920 in exon 31) that changed a highly conserved arginine to glutamine at residual 1307 (p.R1307Q) in patient 1. A heterozygous-missense mutation (c.166 C>T; p.R56W) was identified in DUOXA1 in patient 2. Functional studies demonstrated that both p.R1307Q mutant or p.R56W mutant decreased the DUOX1 expression at mRNA and protein levels, with a corresponding impairment in H 2 O 2 generation ( P < 0.01). The results also showed that intact DUOXA1 was required for full activity of DUOX1 and H 2 O 2 generation. Conclusions: We have identified two heterozygous missense mutations in DUOX1 and DUOXA1 in two patients that can cause CH through disrupting the coordination of DUOX1 and DUOXA1 in the generation of H 2 O 2 . This study for the first time demonstrates that the DUOX1/DUOXA1 system, if genetically defective, can cause CH.

Abstract:The objective of this research is to study the types and characteristics of DEHAL1 gene mutation in patients with congenital hypothyroidism (CH) and thyroid goiter from Shandong Province, which can provide some evidence for gene diagnosis of CH. 47 cases of patients who were diagnosed as CH combined with thyroid goiter by neonatal screening and 100 normal controls were selected as subjects and their genome DNA were extracted. All the exons were amplified by polymerase chain reaction (PCR) and PCR products were sequenced by direct sequencing (Sanger sequencing). DNA sequencing results were compared to the DEHAL1 gene reference sequence to see whether there was mutation, and χ2 test was used on the gene frequency of discovered Single Nucleotide Polymorphisms (SNP). The results showed that no DEHAL1 gene mutation was found in 60 cases of CH with thyroid goiter patients and 100 normal controls, however, two SNPs were found(rs672766, IVS3+129C>T; rs2076292, IVS3+142C>T) in intron region. There was no significant difference between the SNP rate in CH patients and normal controls (P > 0.05). It can be concluded that DEHAL1 gene mutation rate is very low which may not be the main factor leading to the congenital hypothyroidism (CH) with thyroid goiter in Shandong Province, China.

Background: Currently, the long-term prognosis of pancreatic cancer (PC) is difficult to accurately predict. Therefore, the purpose of this study is to identify lncRNA associated with genome instability, and establish genome instability-derived lncRNA signature (GILncSig).Method: Clinical information, RNA-seq expression data and somatic mutation data were acquired from The Cancer Genome Atlas (TCGA) database. The GO and KEEG analysis was applied to built lncRNAs–mRNA co-expression network was associated with the genome instability.Univariate and multivariate Cox proportional hazard regression were used to single out the independently prognostic lncRNA in PC patients. Finally, 9 lncrnas were discovered and incorporated into the construction of GILncSig. Patients were divided into high-risk and low-risk groups based on the median risk score, and Kaplan–Meier survival analysis was used to compare the overall survival between the two groups.Results: KEEG analysis are mainly enriched in a variety of cell signal transduction and metabolism. The risk score of GILncSig was built by 9 lncRNA (SOCS2-AS1, AC127024.6, TRPC7-AS1, AL359504.1, AL117382.2, LYPLAL1-AS1, LINC02014, CASC8, KRT7-AS), and the Kaplan–Meier curve showed that the prognosis of low risk patient were better than high risk patients in the testing group(p=0.003) and the whole TCGA patients(p<0.001). According to the assessment of genome instability, KRAS wide-type patients was divided into two groups, with the genome stable group showing significantly improved outcome and the genome unstable group showing no significant difference compared with those with KRAS mutation.Conclusion: This study provides a prognostic model for predicting the prognosis of PC patients, and introduces reference and evidence of the role of lncRNA in genome instability in the further study.