Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria
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 mechan...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-09-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.01018/full |
| _version_ | 1828937765517000704 |
|---|---|
| author | Yibao Fu Jinmeng Jia Lishu Yue Ruiying Yang Yongli Guo Yongli Guo Yongli Guo Xin Ni Xin Ni Xin Ni Tieliu Shi Tieliu Shi |
| author_facet | Yibao Fu Jinmeng Jia Lishu Yue Ruiying Yang Yongli Guo Yongli Guo Yongli Guo Xin Ni Xin Ni Xin Ni Tieliu Shi Tieliu Shi |
| author_sort | Yibao Fu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T02:31:08Z |
| format | Article |
| id | doaj.art-6dddeeb6dd11467c9a5023bea5866a49 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-14T02:31:08Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-6dddeeb6dd11467c9a5023bea5866a492022-12-21T23:20:16ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-09-011010.3389/fphar.2019.01018437241Systematically Analyzing the Pathogenic Variations for Acute Intermittent PorphyriaYibao Fu0Jinmeng Jia1Lishu Yue2Ruiying Yang3Yongli Guo4Yongli Guo5Yongli Guo6Xin Ni7Xin Ni8Xin Ni9Tieliu Shi10Tieliu Shi11Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, ChinaCenter for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, ChinaCenter for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, ChinaCenter for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, ChinaBig 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, ChinaBiobank 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, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, ChinaBig 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, ChinaBiobank 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, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, ChinaCenter for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, ChinaNational 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, ChinaThe 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.https://www.frontiersin.org/article/10.3389/fphar.2019.01018/fullacute intermittent porphyriaHMBS genegenotype and phenotype relationshiphypergeometric testvariation ethnic distribution differencePPARA gene |
| spellingShingle | Yibao Fu Jinmeng Jia Lishu Yue Ruiying Yang Yongli Guo Yongli Guo Yongli Guo Xin Ni Xin Ni Xin Ni Tieliu Shi Tieliu Shi Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria Frontiers in Pharmacology acute intermittent porphyria HMBS gene genotype and phenotype relationship hypergeometric test variation ethnic distribution difference PPARA gene |
| title | Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria |
| title_full | Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria |
| title_fullStr | Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria |
| title_full_unstemmed | Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria |
| title_short | Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria |
| title_sort | systematically analyzing the pathogenic variations for acute intermittent porphyria |
| topic | acute intermittent porphyria HMBS gene genotype and phenotype relationship hypergeometric test variation ethnic distribution difference PPARA gene |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.01018/full |
| work_keys_str_mv | AT yibaofu systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT jinmengjia systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT lishuyue systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT ruiyingyang systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT yongliguo systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT yongliguo systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT yongliguo systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT xinni systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT xinni systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT xinni systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT tieliushi systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria AT tieliushi systematicallyanalyzingthepathogenicvariationsforacuteintermittentporphyria |