Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria.

Yibao Fu,Ruiying Yang,Xin Ni,Lishu Yue,Jinmeng Jia,Tieliu Shi,Yongli Guo

doi:10.3389/fphar.2019.01018

Abstract

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.

Highlights

Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder caused by the deficient activity of hydroxymethylbilane synthase (HMBS), which is referred as porphobilinogen deaminase (PBGD), the third enzyme in the pathway of heme biosynthetic (Gill et al, 2009; Chen et al, 2018)
It is commonly recognized that sex steroids play an important role for the clinical manifestations in porphyria in women and they act as inducers in heme biosynthesis (Innala et al, 2010)
We studied the interactions between different amino acid residues using the Residue Interaction Network Generator (RING) and interpreted the interrelation between different residues, including 5M7F (Human porphobilinogen deaminase in complex with DPM cofactor) and 5M6R (Human porphobilinogen deaminase in complex with reaction intermediate)

Summary

Introduction

Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder caused by the deficient activity of hydroxymethylbilane synthase (HMBS), which is referred as porphobilinogen deaminase (PBGD), the third enzyme in the pathway of heme biosynthetic (Gill et al, 2009; Chen et al, 2018). The clinical symptoms of AIP patients include acute recurrent abdominal pain, and often are accompanied by gastrointestinal disorders such as nausea, vomiting and constipation (Yang et al, 2015; Yang et al, 2016; Duque-Serrano et al, 2018). Most of the clinical features of an attack are caused by the effects on the nervous system and the characteristics of the symptoms are not so obvious (Stein et al, 2017). This is one of the reasons why it can be misdiagnosed.

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Results

Conclusion