RAPID: Resource of Asian Primary Immunodeficiency Diseases.

Availability of a freely accessible, dynamic and integrated database for primary immunodeficiency diseases (PID) is important both for researchers as well as clinicians. To build a PID informational platform and also as a part of action to initiate a network of PID research in Asia, we have constructed a web-based compendium of molecular alterations in PID, named Resource of Asian Primary Immunodeficiency Diseases (RAPID), which is available as a worldwide web resource at http://rapid.rcai.riken.jp/. It hosts information on sequence variations and expression at the mRNA and protein levels of all genes reported to be involved in PID patients. The main objective of this database is to provide detailed information pertaining to genes and proteins involved in primary immunodeficiency diseases along with other relevant information about protein-protein interactions, mouse studies and microarray gene-expression profiles in various organs and cells of the immune system. RAPID also hosts a tool, mutation viewer, to predict deleterious and novel mutations and also to obtain mutation-based 3D structures for PID genes. Thus, information contained in this database should help physicians and other biomedical investigators to further investigate the role of these molecules in PID.

INTRODUCTION

Primary immunodeficiency diseases (PIDs) are a class of disorders resulting from intrinsic defects in genes involved in the development and maintenance of the immune system. More than 150 primary immunodeficiency genes are reported thus far, which are classified into eight different categories by the International Union of Immunological Societies (1). Patients with these intrinsic defects have increased susceptibility to recurrent and persistent infections, and they may also have autoimmune and cancer-related symptoms. Most PIDs are rare and the diagnosed patients for a given condition are often randomly spread out around the world (2). The genetic defects that cause PIDs can affect the expression and function of proteins that are involved in a range of biological process such as immune development, effector-cell functions, signaling cascades and maintenance of immune homeostasis (3). Recent advances in both diagnosis and therapeutic modalities have allowed these defects to be identified earlier and to be more precisely defined, and they have also resulted in more promising long-term outcomes (4). Development of a freely accessible, dynamic and integrated database with inclusion of genomics, transcriptomics and proteomics data of all genes that are involved in PID has the potential to further accelerate research into PIDs as well as provide physicians with easy access to pertinent clinical and molecular data that is otherwise spread throughout the literature.

Resource of Asian Primary Immunodeficiency Diseases (RAPID) is a web-based compendium of molecular alterations in PIDs that is freely available to the academic community at http://rapid.rcai.riken.jp. It hosts information on the sequence variations mapped to the mRNA and protein sequences for all the genes reported from PID patients worldwide. Besides molecular alterations, RAPID has the protein–protein interaction network from Human Protein Reference Database (HPRD) (5), a database with protein-centric information for all human proteins, along with a graphical representation of the expression of PID genes from microarray profiling of organs and cells of the immune system from Gene Expression Omnibus (GEO) (6) and Reference Database of Immune Cells (RefDIC) (7). In addition, it incorporates mouse studies from Mouse Genome Informatics (MGI) (8) database for the representation of allele-based phenotypes and anatomical systems affected due to either mouse knockouts, knockins and spontaneous mutations for the available PID genes. With inclusion of this variety of data for the PID disease genes, RAPID can serve as a connecting link between the genotype and the phenotype.

RAPID ARCHITECTURE

RAPID is an object-oriented database. We used Zope (http://www.zope.org) for the development of RAPID. Zope is a leading open source web application server and is built using the programming language Python (http://www.python.org). MySQL is used as a backend data storage system.

RAPID allows users access to gene-specific PID information either by using the query page or by browsing. RAPID can be queried by various search options including gene symbol, protein name, mouse phenotypes, chromosome number and PID category, and accession numbers of entries from several database resources. The query system includes an autocomplete option that facilitates quick access to the list of items in the database. Users can browse this resource by PID genes, mutation features such as mutation types and effects. This is the first of its kind database to have these user-friendly features for search and display options.

Primary information page is the default main page of every PID gene in the RAPID. It summarizes the external links available in the public domain such as Entrez (9,10), HPRD, IDR, RefDIC, NetPath, OMIM (11), HGNC (12), PDB (13), Ensembl (14) and UniProt/Swiss-Prot (15). It also includes the disease phenotype linked to the given gene along with the mode of inheritance, alternative names of the gene function and the associated features (Figure 1A).

Figure 1.

A screenshot of the primary information page and mutation data of WAS gene in RAPID. (A) Primary information of WAS gene along with its external resources to IDR (Immunodeficiency resource) and RefDIC (Reference database of Immune cells) is shown. (B) Mutation data curated from the literature reading is shown along with the mutation viewer tool called ‘Mutation@A Glance’ to visualize the mutations both at DNA and protein levels.

ANNOTATION OF MUTATION DATA

The sequence variations in PID genes reported from the patients are manually curated by expert biologists from the published literature and mapped to the NCBI RefSeq (16,17) genomic, cDNA and protein sequences to aid the scientific community as per the recommendations for the description of sequence variants by Human Genome Variation Society (HGVS) whose main objectives remain to ensure documentation, collection and free distribution of all variation information (18,19). The main criterion for inclusion of mutation data in the RAPID from the literature is that the PID causing genes mutation analysis has to be performed in patient samples who have already presented with a set of PID clinical presentations or associated features or from cell lines derived from such patients. Carriers and asymptomatic individuals are not included in our annotations.

MUTATION VIEWER

Each entry on the mutation has a link to the mutation viewer, a web-based graphical user interface (GUI) enabled tool named Mutation@A Glance, which can be accessed at http://rapid.rcai.riken.jp/mutBrowse.cgi (Figure 1B). It allows users to visualize the mutation position both at the level of DNA and protein sequences as well as homology based 3D structures with various types of information such as SNP, protein domains and functional sites (Hijikata, et al., manuscript in preparation).

GENE-EXPRESSION PROFILES

Gene-expression profiles of PID genes in various organs and cells of the immune systems from a number of microarray experiments available in public repositories are represented graphically for the available PID gene in the form of histograms with immune cell types along with the corresponding average gene-expression intensity values. This shows the expression pattern of these genes in immune cells, which is of relevance to immunologists (Figure 2A).

Figure 2.

A screenshot of the expression profile, interaction network and mouse studies of WAS gene. (A) Microarray gene expression profile of WAS gene in a particular human microarray data set from GEO. (B) Interaction networks of WAS from HPRD is shown along with the legends, which explain various parameters of interactors in different shapes and colors. (C) Primary information of mouse gene WAS is shown along with anatomical systems affected due to mutations and its allelic composition and phenotypes from MGI database.

INTERACTION NETWORKS

All the primary immunodeficiency disease genes have been mapped to their direct physical interactors and, in turn, these interactors are represented differently based on whether an interactor is already known to be PID or not, any of these interactors have their site of expression in immune cells, or any lethality and/or immune system/hematopoietic phenotypes affected due to either mouse knockout, or spontaneous mutation in mice. This information is graphically represented in the form of nodes and edges with each node having different shapes and colors based on the aforementioned parameters (Figure 2B).

MOUSE STUDIES

The experimental designs to study the effect of the gene variations on the disease phenotype are complicated by the availability of ideal control subjects in case of humans. Mouse models of human diseases are widely used to study genotype–phenotype correlations. In RAPID, all available PID genes are mapped to their corresponding mouse ortholog from MGI to catalog any lethality and/or immune system/hematopoietic phenotypes resulting from knockout of genes or spontaneous mutations (Figure 2C). These features are organized and represented in such a way that RAPID should serve as a discovery tool for prediction of candidate PID genes, a useful feature for immunologists, physicians and researchers.

RAPID STATISTICS

At present, RAPID comprises total of 161 PID genes that are involved in PID, out of which 143 PID genes are reported with over 2455 unique mutation data. Table 1 shows the overall statistics of RAPID as of August 2008.

Table 1.

Overall statistics

Number of PID genes	161
Number of PID genes with mutation data	143
Number of non-redundant mutation entries	2455
Number of unique PubMed citations	762

FUTURE DEVELOPMENTS

In addition to keeping this resource updated on a regular basis and further elucidation of role of PID genes at molecular level, we will initiate global community standard formats for PID data exchange and validation. We will also incorporate standardized DNA diagnosis protocols for screening common PID, which will allow this database to serve as an integrated informational platform for genomics-based PID diagnosis.

CONCLUSIONS

RAPID provides information in an easily accessible and decipherable ways for all users. We support and encourage the input from PID physicians and researcher to share their experiences in standardizing vocabulary terms for representing anonymous patient clinical data that enables RAPID to be used as a diagnostic tool among physicians for early diagnosis and effective treatments for PID patients. With community participation of interested groups, we anticipate that RAPID will become a primary resource of PIDs in Asia.

FUNDING

The Special Coordination Funds for promoting Science and Technology, from the Ministry of Education, Culture, Sports, and Science of Japan. Funding for open access charge: RIKEN Research Center for Allergy and Immunology.

Conflict of interest statement. None declared.