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Open access

Feng Sun, Jun-Xiu Zhang, Chang-Yi Yang, Guan-Qi Gao, Wen-Bin Zhu, Bing Han, Le-Le Zhang, Yue-Yue Wan, Xiao-Ping Ye, Yu-Ru Ma, Man-Man Zhang, Liu Yang, Qian-Yue Zhang, Wei Liu, Cui-Cui Guo, Gang Chen, Shuang-Xia Zhao, Ke-Yi Song, and Huai-Dong Song

Objective

Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited.

Design and methods

One hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees.

Results

Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands.

Conclusions

Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.

Restricted access

Zhen-Jie Tong, Chin-Wei Kuo, Po-Cheng Yen, Chih-Ching Lin, Ming-Tsun Tsai, Shing-Hwa Lu, Yi-Ping Chang, Wen-Sheng Liu, Han-Hsing Tsou, Hsiao-Wei Cheng, and Hsiang-Tsui Wang

Objective

Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a major chronic complication of diabetes and is the most frequent cause of kidney failure globally. A better understanding of the pathophysiology of DN would lead to the development of novel therapeutic options. Acrolein, an α,β-unsaturated aldehyde, is a common dietary and environmental pollutant.

Design

The role of acrolein and the potential protective action of acrolein scavengers in DN were investigated using high-fat diet/ streptozotocin-induced DN mice and in vitro DN cellular models.

Methods

Acrolein-protein conjugates (Acr-PCs) in kidney tissues were examined using immunohistochemistry. Renin–angiotensin system (RAS) and downstream signaling pathways were analyzed using quantitative RT-PCR and Western blot analyses. Acr-PCs in DN patients were analyzed using an established Acr-PC ELISA system.

Results

We found an increase in Acr-PCs in kidney cells using in vivo and in vitro DN models. Hyperglycemia activated the RAS and downstream MAPK pathways, increasing inflammatory cytokines and cellular apoptosis in two human kidney cell lines (HK2 and HEK293). A similar effect was induced by acrolein. Furthermore, acrolein scavengers such as N-acetylcysteine, hydralazine, and carnosine could ameliorate diabetes-induced kidney injury. Clinically, we also found increased Acr-PCs in serum samples or kidney tissues of DKD patients compared to normal volunteers, and the Acr-PCs were negatively correlated with kidney function.

Conclusions

These results together suggest that acrolein plays a role in the pathogenesis of DN and could be a diagnostic marker and effective therapeutic target to ameliorate the development of DN.