Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria

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.

Identification of risk features for complication in Gaucher’s disease patients: a machine learning analysis of the Spanish registry of Gaucher disease

“…This methodology is especially useful for obtaining pooled information on the diversity of outcomes and identifying prognostic factors potentially related to disease complications [ 35 ]. In rare disease research, this is of particular interest due to the scarcity and the spread of the data among the different centers [ 36 ]. Various approaches have been applied in the area of rare diseases, especially in looking for genetic associations [ 37 ] and making correlations between genotype and phenotype [ 38 ].…”

Recent advances in the epidemiology and genetics of acute intermittent porphyria

“…Although a study in Finland found similar genotypes, penetrance differed greatly among families (32). This shows that the phenotype of AIP is not determined by the HMBS genotype alone but that other factors such as modifying genes and the environment also play a vital role in the pathogenesis of AIP attacks (6,24,25,32,70,71 (72). The correlation between genotype and phenotype is still a topic of interest in research on AIP.…”

Identification of risk features for complication in Gaucher’s Disease patients: A Machine Learning analysis of the Spanish Registry of Gaucher Disease.

“…This methodology is especially useful for obtaining pooled information on the diversity of outcomes and identifying prognostic factors potentially related to disease complications (35). In rare disease research, this is of particular interest due to the scarcity and the spread of the data among the different centers (36). Various approaches have been applied in the area of rare diseases, especially in looking for genetic associations (37) and making correlations between genotype and phenotype (38).…”