PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways

PANTHER is a freely available, comprehensive software system for relating protein sequence evolution to the evolution of specific protein functions and biological roles. Since 2005, there have been three main improvements to PANTHER. First, the sequences used to create evolutionary trees are carefully selected to provide coverage of phylogenetic as well as functional information. Second, PANTHER is now a member of the InterPro Consortium, and the PANTHER hidden markov Models (HMMs) are distributed as part of InterProScan. Third, we have dramatically expanded the number of pathways associated with subfamilies in PANTHER. Pathways provide a detailed, structured representation of protein function in the context of biological reaction networks. PANTHER pathways were generated using the emerging Systems Biology Markup Language (SBML) standard using pathway network editing software called CellDesigner. The pathway collection currently contains ∼1500 reactions in 130 pathways, curated by expert biologists with authorship attribution. The curation environment is designed to be easy to use, and the number of pathways is growing steadily. Because the reaction participants are linked to subfamilies and corresponding HMMs, reactions can be inferred across numerous different organisms. The HMMs can be downloaded by FTP, and tools for analyzing data in the context of pathways and function ontologies are available at

Prevalence of Connective Tissue Diseases in Egyptian Patients Presenting with Fever of Unknown Origin

Objective To estimate the prevalence of connective tissue diseases in patients presenting with fever of unknown origin (FUO). Patients and Methods In this study thirty patients diagnosed as FUO (Group 1), in 2008, were included in an observational study and diagnostic workup. Additionally, retrospective analysis of seventy patients’ files (Group 2), for patients who presented with prolonged unexplained pyrexia to the same hospital in the previous two years, was performed. Patients were subjected to: full clinical assessment including full history taking, thorough clinical examination, laboratory investigations including the basic investigations for patients with prolonged fever, complete blood count, erythrocytes sedimentation rate, urine analysis and culture, blood culture, sputum culture and plain chest X ray. Further diagnostic work up and/or procedures were requested according to the potential diagnostic clues (PDC) present in every patient. Results Out of 100 FUO patients, 50% were found to have infectious diseases, 24% were found to have connective tissue diseases, 8% miscellaneous causes and 7% neoplastic diseases ( P < 0.05). In 11 patients no definite cause for FUO could be identified. Connective tissue patients were: eight systemic lupus patients (33.3%), five patients with familial mediterranean fever (20.8%), four patients with rheumatoid arthritis (16.6%), three patients (12.5%) with Still's disease and Rheumatic fever and one patient with Behçet syndrome/Crohn's disease (4.3%), ( P < 0.05). Conclusions Despite the advanced technology, FUO remains a challenging medical problem. Infections were the most common cause of FUO in Egypt, confirming the trends found in other parts of the world. There was an increased prevalence of connective tissue patients presented with prolonged unexplained fever. A keen clinical eye, meticulous history taking and repeated physical examination remained the most important diagnostic tools in FUO patients

Accurate Prediction of the Functional Significance of Single Nucleotide Polymorphisms and Mutations in the ABCA1 Gene

The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r (2) = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation

Applications for protein sequence–function evolution data: mRNA/protein expression analysis and coding SNP scoring tools

The vast amount of protein sequence data now available, together with accumulating experimental knowledge of protein function, enables modeling of protein sequence and function evolution. The PANTHER database was designed to model evolutionary sequence–function relationships on a large scale. There are a number of applications for these data, and we have implemented web services that address three of them. The first is a protein classification service. Proteins can be classified, using only their amino acid sequences, to evolutionary groups at both the family and subfamily levels. Specific subfamilies, and often families, are further classified when possible according to their functions, including molecular function and the biological processes and pathways they participate in. The second application, then, is an expression data analysis service, where functional classification information can help find biological patterns in the data obtained from genome-wide experiments. The third application is a coding single-nucleotide polymorphism scoring service. In this case, information about evolutionarily related proteins is used to assess the likelihood of a deleterious effect on protein function arising from a single substitution at a specific amino acid position in the protein. All three web services are available at

The PANTHER database of protein families, subfamilies, functions and pathways

PANTHER is a large collection of protein families that have been subdivided into functionally related subfamilies, using human expertise. These subfamilies model the divergence of specific functions within protein families, allowing more accurate association with function (ontology terms and pathways), as well as inference of amino acids important for functional specificity. Hidden Markov models (HMMs) are built for each family and subfamily for classifying additional protein sequences. The latest version, 5.0, contains 6683 protein families, divided into 31 705 subfamilies, covering ∼90% of mammalian protein-coding genes. PANTHER 5.0 includes a number of significant improvements over previous versions, most notably (i) representation of pathways (primarily signaling pathways) and association with subfamilies and individual protein sequences; (ii) an improved methodology for defining the PANTHER families and subfamilies, and for building the HMMs; (iii) resources for scoring sequences against PANTHER HMMs both over the web and locally; and (iv) a number of new web resources to facilitate analysis of large gene lists, including data generated from high-throughput expression experiments. Efforts are underway to add PANTHER to the InterPro suite of databases, and to make PANTHER consistent with the PIRSF database. PANTHER is now publicly available without restriction at http://panther.appliedbiosystems.com

New developments in the InterPro database

InterPro is an integrated resource for protein families, domains and functional sites, which integrates the following protein signature databases: PROSITE, PRINTS, ProDom, Pfam, SMART, TIGRFAMs, PIRSF, SUPERFAMILY, Gene3D and PANTHER. The latter two new member databases have been integrated since the last publication in this journal. There have been several new developments in InterPro, including an additional reading field, new database links, extensions to the web interface and additional match XML files. InterPro has always provided matches to UniProtKB proteins on the website and in the match XML file on the FTP site. Additional matches to proteins in UniParc (UniProt archive) are now available for download in the new match XML files only. The latest InterPro release (13.0) contains more than 13 000 entries, covering over 78% of all proteins in UniProtKB. The database is available for text- and sequence-based searches via a webserver (), and for download by anonymous FTP (). The InterProScan search tool is now also available via a web service at

Case Report - Fallot's Tetralogy Presenting With Variceal Bleed

The erythrocytosis of Fallot's tetralogy may lead to spontaneous thrombosis at any site, but splenic vein thrombosis and variceal bleed is rarely a presentation of Fallot's tetralogy. A case of a 48 years old female with undiagnosed Fallot's tetralogy, presenting with variceal bleed due to splenic vein thrombosis, is reported. It is also interesting to note that the patient survived till this age without any medical or surgical treatment