Phylogenetic analysis of Na+/K+ ATPase: Insight into the mechanism for the genesis of multi-isoforms of protein complex

One most notable trend during the evolution is the substantial expansion of genomes along with dramatic expansion of protein diversity. It has been discovered that, whilst in prokaryotes subunits of many proteinases axe encoded by single genes, these are mostly encoded by multi-genes in eukaryotes. To understand the mechanism for the genesis of multi-isoforms of protein complex, we have analyzed amino acid sequences of Na+/K+ ATPase from various species ranging from archaea to vertebrates. Phylogenetic relationship between the selected species was considered from the perspective of important functional domains of Na+/K+ ATPase including cation ATPase N termination, E1-E2 ATPase, hydrolase, and cation ATPase C termination of the a subunit, Na+/K+ ATPase of the beta subunit, and ATP1G1_PLM_MAT8 of the gamma subunit. Coincident trees, obtained through comparison of aforementioned domains of the alpha and beta subunits, were used to examine the evolutionary divergence. By conservational and phylogenetic analyses, evolution of the Na+/K+ ATPase was outlined. Evidence was also found that essential domains of the Na+/K+ ATPase have been conserved during the evolution. These investigations seem to imply that various isoforms of alpha and beta subunits of vertebral Na+/K+ ATPases have evolved from single ancestral alpha and beta subunit genes through duplication events. In addition, our results seem to suggest a third fate for duplicated genes, e.g. the duplicate may have the same function as their ancestor gene. The results may also provide important clues to the underlying mechanisms of genesis of Na+/K+ ATPase multi-isoforms

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88

Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4). Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list). </p

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology