Tao Wang1, Sisi Ding2, Sicheng Li1, Heming Guo1, Xiaohong Chen1, Yun Huang1, Jian Huang3, Jianwu Wu4, Cheng Hu5, Chen Fang6, Ji Hu7. 1. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, 215004, Suzhou, China. 2. Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No.708 Ren-min Road, Suzhou, China. 3. School of Basic Medicine and Biological Sciences, Medical College of Soochow University, 215123, Suzhou, China. 4. Department of General Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, 215002, Suzhou, China. 5. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233, Shanghai, China. 6. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, 215004, Suzhou, China. afa9911@sina.com. 7. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, 215004, Suzhou, China. huji@suda.edu.cn.
Abstract
PURPOSE: Neonatal diabetes mellitus (NDM) is caused by mutations in the genes responsible for pancreatic β cell mass or function. This study aimed to screen the mutations in the KCNJ11, ABCC8, and INS genes in a Chinese patient with clinical features of NDM. METHODS: The entire coding sequence and exon/intron boundaries of KCNJ11, ABCC8, and INS genes were detected by Sanger sequencing. The pathogenicity of the mutation was determined by using online prediction programs SIFT and Mutation Taser. The conformational alterations which contribute to the change of protein function were analyzed at the structural level. RESULTS: A novel mutation L35Q (B11) of the INS gene was discovered in the patient. As L35 residue contributes to its hydrophobic core of the protein, the L35Q substitution is predicated to affect B19-A20 disulfide bond and therefore disrupt the folding of the proinsulin, which ultimately results in beta cell apoptosis by inducing ER stress. CONCLUSIONS: This case could help us understand the role of the INS mutation in the development of diabetes.
PURPOSE:Neonatal diabetes mellitus (NDM) is caused by mutations in the genes responsible for pancreatic β cell mass or function. This study aimed to screen the mutations in the KCNJ11, ABCC8, and INS genes in a Chinese patient with clinical features of NDM. METHODS: The entire coding sequence and exon/intron boundaries of KCNJ11, ABCC8, and INS genes were detected by Sanger sequencing. The pathogenicity of the mutation was determined by using online prediction programs SIFT and Mutation Taser. The conformational alterations which contribute to the change of protein function were analyzed at the structural level. RESULTS: A novel mutation L35Q (B11) of the INS gene was discovered in the patient. As L35 residue contributes to its hydrophobic core of the protein, the L35Q substitution is predicated to affect B19-A20 disulfide bond and therefore disrupt the folding of the proinsulin, which ultimately results in beta cell apoptosis by inducing ER stress. CONCLUSIONS: This case could help us understand the role of the INS mutation in the development of diabetes.
Entities:
Keywords:
Diabetes related complications; INS mutation; Molecular model; Neonatal diabetes mellitus
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