Original Research ARTICLE
Systematically analyzing the pathogenic variations for Acute Intermittent Porphyria
- 1East China Normal University, China
- 2Beijing Institute of Otorhinolaryngology,Beijing Tongren Hospital, Capital Medical University, China
- 3Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences,, East China Normal University, 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.
Keywords: Acute intermittent porphyria, HMBS gene, Variation ethnic distribution difference, Hypergeometric test, genotype and phenotype relationship, PPARA gene
Received: 16 Nov 2018;
Accepted: 09 Aug 2019.
Copyright: © 2019 Fu, Yue, Yang, Jia, Guo, Ni and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dr. Yongli Guo, Beijing Institute of Otorhinolaryngology,Beijing Tongren Hospital, Capital Medical University, Beijing, China, email@example.com
Dr. Xin Ni, Beijing Institute of Otorhinolaryngology,Beijing Tongren Hospital, Capital Medical University, Beijing, China, firstname.lastname@example.org
Prof. Tieliu Shi, East China Normal University, Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences,, Shanghai, 200062, Shanghai Municipality, China, email@example.com