机构：[1]Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China,[2]Big Data and Engineering Research Center, Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, National Center for Children’s Health, Beijing Pediatric Research Institute, Capital Medical University, Beijing, China,临床科室科研平台职能科室耳鼻咽喉头颈外科临床流行病与循证医学中心儿科研究所首都医科大学附属北京儿童医院[3]Biobank for Clinical Data and Samples in Pediatrics, Beijing Children’s Hospital, National Center for Children’s Health, Beijing Pediatric Research Institute, Capital Medical University, Beijing, China,科研平台职能科室临床流行病与循证医学中心儿科研究所首都医科大学附属北京儿童医院[4]Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China,临床科室职能科室耳鼻咽喉头颈外科临床流行病与循证医学中心首都医科大学附属北京儿童医院[5]National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, China
The rare autosomal dominant disorder acute intermittent porphyria (AIP) is caused by the deficient activity of hydroxymethylbilane synthase (HMBS). The symptoms of AIP are acute neurovisceral attacks which are induced by the dysfunction of heme biosynthesis. To better interpret the underlying mechanism of clinical phenotypes, we collected 117 HMBS gene mutations from reported individuals with AIP and evaluated the mutations' impacts on the corresponding protein structure and function. We found that several mutations with most severe clinical symptoms are located at dipyromethane cofactor (DPM) binding domain of HMBS. Mutations on these residues likely significantly influence the catalytic reaction. To infer new pathogenic mutations, we evaluated the pathogenicity for all the possible missense mutations of HMBS gene with different bioinformatic prediction algorithms, and identified 34 mutations with serious pathogenicity and low allele frequency. In addition, we found that gene PPARA may also play an important role in the mechanisms of AIP attacks. Our analysis about the distribution frequencies of the 23 variations revealed different distribution patterns among eight ethnic populations, which could help to explain the genetic basis that may contribute to population disparities in AIP prevalence. Our systematic analysis provides a better understanding for this disease and helps for the diagnosis and treatment of AIP.
基金：
China Human Proteome Project [2014DFB30010, 2014DFB30030]; National High Technology Research and Development Program of China (863 project)National High Technology Research and Development Program of China [2015AA020108]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [31671377, 81472369, 81502144]; Clinical Application Research Funds of Capital Beijing [Z171100001017051]; Beihang University & Capital Medical University Advanced Innovation Center for Big Data-Based Precision Medicine Plan [BHME-201801]; Shanghai 111 Project [B14019]
第一作者机构：[1]Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China,
通讯作者：
通讯机构：[1]Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China,[2]Big Data and Engineering Research Center, Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, National Center for Children’s Health, Beijing Pediatric Research Institute, Capital Medical University, Beijing, China,[3]Biobank for Clinical Data and Samples in Pediatrics, Beijing Children’s Hospital, National Center for Children’s Health, Beijing Pediatric Research Institute, Capital Medical University, Beijing, China,[4]Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China,[5]National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, China
推荐引用方式(GB/T 7714)：
Fu Yibao,Jia Jinmeng,Yue Lishu,et al.Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria[J].Frontiers in pharmacology.2019,10:-.doi:10.3389/fphar.2019.01018.
APA：
Fu, Yibao,Jia, Jinmeng,Yue, Lishu,Yang, Ruiying,Guo, Yongli...&Shi, Tieliu.(2019).Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria.Frontiers in pharmacology,10,
MLA：
Fu, Yibao,et al."Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria".Frontiers in pharmacology 10.(2019):-
