Galactosemia type 2 is an autosomal recessive disorder characterized by the deficiency of galactokinase (GALK) enzyme due to missense mutations in GALK1 gene, which is associated with various manifestations such as hyper galactosemia and formation of cataracts. GALK enzyme catalyzes the adenosine triphosphate (ATP)-dependent phosphorylation of α-d-galactose to galactose-1-phosphate. We searched 4 different literature databases (Google Scholar, PubMed, PubMed Central, and Science Direct) and 3 gene-variant databases (Online Mendelian Inheritance in Man, Human Gene Mutation Database, and UniProt) to collect all the reported missense mutations associated with GALK deficiency. Our search strategy yielded 32 missense mutations. We used several computational tools (pathogenicity and stability, biophysical characterization, and physiochemical analyses) to prioritize the most significant mutations for further analyses. On the basis of the pathogenicity and stability predictions, 3 mutations (P28T, A198V, and L139P) were chosen to be tested further for physicochemical characterization, molecular docking, and simulation analyses. Molecular docking analysis revealed a decrease in interaction between the protein and ATP in all the 3 mutations, and molecular dynamic simulations of 50 ns showed a loss of stability and compactness in the mutant proteins. As the next step, comparative physicochemical changes of the native and the mutant proteins were carried out using essential dynamics. Overall, P28T and A198V were predicted to alter the structure and function of GALK protein when compared to the mutant L139P. This study demonstrates the power of computational analysis in variant classification and interpretation and provides a platform for developing targeted therapeutics.

Pemphigus vulgaris (PV) is a rare autoimmune blistering disorder, which could affect both skin and mucosal surfaces. There is increasing evidence that genetics plays a critical role in PV development, severity and prognosis. Single‐nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people and have been widely evaluated in most diseases. However, there are few studies regarding the roles of SNPs in the PV. Here, we reviewed both pathogenic and protective roles of the SNPs in non‐HLA genes regarding the PV. Among the large number of studied SNPs, it was found that several SNPs in different genes might control the susceptibility of PV, including TNFA (rs361525, rs1800629, rs1800629), IL10 (rs1800871, rs1800896, rs1800871, and rs1800872), IL6 (rs1800795), CTLA4 (rs231775), ICOS (rs10932029), CD86 (rs1129055), DSG3 (rs8085532, rs3911655, rs3848485, rs3794925, rs1466379), ST18 (rs2304365, rs17315309) and TAP2 (rs7454108), probably in a population‐specific manner. Moreover, SNPs in glucocorticoid receptor, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, including rs11745958, rs17209237, rs33388, rs7701443 as well as rs116855232 at NUDT15, seem to be associated with therapeutic outcomes in PV patients. Additionally, variations in the other genes involved in the drugs' metabolisms, pharmacokinetics and pharmacodynamics such as rs396991 in FCGR3A gene could be used for the prediction of clinical response to drugs and side effects. Taken together, SNPs seem to be valuable tools for better management of PV patients. Further studies need to be conducted to evaluate SNPs in genes that control immune responses and apoptosis.

Background TH17/IL‐23 immune axis is considered to be involved in the pathogenesis of autoimmune and chronic inflammatory diseases. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease, characterized by the presence of autoantibodies against the components of the dermal‐epidermal junction. Animal studies and characterization of patient samples point toward a contribution of TH17 cells in BP pathogenesis. However, genetic polymorphisms in the genes of TH17/IL‐23 cytokines have not yet been well investigated in BP. Methods Detection of polymorphisms in IL‐17A (rs2275913 and rs3819025), IL‐17F (rs2397084 and rs763780), IL‐17RA (rs2229151), and IL‐23R (rs2201841, rs7530511, rs11209026, and rs10889677) genes were performed following the collection of blood samples and DNA extraction from BP patients and controls. Gene expression of IL‐23R was determined by quantitative RT‐PCR analysis. Results The prevalence of IL‐23R rs7530511 genotypes and alleles, as well as IL‐23R rs2201841 alleles, is significantly different between the BP patients and controls. While the minor C‐allele of IL‐23R rs7530511 is highly present in the patients, the G‐allele distribution of IL‐23R rs2201841 is significantly more prevalent in the control individuals compared to the BP patients. Genotypes and alleles of other SNPs in IL‐17A, IL‐17F, and IL‐17RA were similarly distributed in patients and controls. Conclusions No alteration was found in the gene expression between wild and polymorphic genotypes of IL‐23R (rs2201841 and rs7530511) variations, indicating they do not contribute to altering the levels of gene expression in blood. In summary, our data show that the alleles of two SNPs in IL‐23R rs2201841 and rs7530511 are associated with BP.

TNF-α -308G/A polymorphism is not associated with the risk to develop of BP and AA in our Iranian cohort. Furthermore, this polymorphism is contributed to altering the levels of gene expression in BP disease.