Software and database for the analysis of mutations in the VHL gene.

VHL is a tumor suppressor gene localized on chromosome 3p25-26. Mutations of the VHL gene were described at first in the heritable von Hippel-Lindau disease and in the sporadic Renal Cell Carcinoma (RCC). More recently, VHL has also been shown to harbor mutations in mesothelioma and small cell lung carcinoma. To date more than 500 mutations have been identified. These mutations are mainly private with only one hot spot at codon 167 associated with pheochromocytoma. The germline mutations are essentially missense while somatic mutations include deletions, insertions and nonsense. To standardize the collection of these informations, facilitate the mutational analysis of the VHL gene and promote the genotype-phenotype analysis, a software package along with a computerized database have been created. The current database and the analysis software are accessible via the internet and world wide web interface at the URL:http://www.umd.necker.fr     

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr     

APC gene: database of germline and somatic mutations in human tumors and cell lines.

A database (http://perso.curie.fr/tsoussi ) is described, in which over 1000 mutations in the human APC gene of tumors (colon cancer predominantly) are compiled from the literature. It includes both molecular information about the mutations and clinical data about the patients. Software has been designed to analyse all this information in the database.     

IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools.

Since 1989, about 570 different p53 mutations have been identified in more than 8000 human cancers. A database of these mutations was initiated by M. Hollstein and C. C. Harris in 1990. This database originally consisted of a list of somatic point mutations in the p 53 gene of human tumors and cell lines, compiled from the published literature and made available in a standard electronic form. The database is maintained at the International Agency for Research on Cancer (IARC) and updated versions are released twice a year (January and July). The current version (July 1997) contains records on 6800 published mutations and will surpass the 8000 mark in the January 1998 release. The database now contains information on somatic and germline mutations in a new format to facilitate data retrieval. In addition, new tools are constructed to improve data analysis, such as a Mutation Viewer Java applet developed at the European Bioinformatics Institute (EBI) to visualise the location and impact of mutations on p53 protein structure. The database is available in different electronic formats at IARC (http://www.iarc. fr/p53/homepage.htm ) or from the EBI server (http://www.ebi.ac.uk ). The IARC p53 website also provides reports on database analysis and links with other p53 sites as well as with related databases. In this report, we describe the criteria for inclusion of data, the revised format and the new visualisation tools. We also briefly discuss the relevance of p 53 mutations to clinical and biological questions.     

Minireview: Constitutively Active G Protein-Coupled Receptors: Potential Mechanisms of Receptor Activation

Abstract

Mutations of G protein-coupled receptors can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis, others occur spontaneously in human diseases. The analysis of the constitutively active G protein-coupled receptors has provided important informations about the molecular mechanisms underlying receptor activation and drug action.     

The fibril_one on-line database: mutations,experimental conditions,and trends associated with amyloid fibril formation

The association of amyloid fibril formation with a number of important diseases, and the extensive study of this process in vitro, has resulted in a large literature containing a vast amount of information about the fibril formation process. This includes mutations and experimental conditions that promote or protect against fibril formation. A database (fibril_one) was designed to hold information relating to the formation of fibrils. It was populated by extensive searches of the literature and other databases. A powerful World Wide Web query interface to the database was developed, enabling a simple and effective method to view amyloidogenic mutations associated with specific proteins. The Web interface was used to identify trends in the data. This revealed that mutations promoting fibril formation through altered folding tend to be associated with destabilization of the native fold. In particular, tendencies of mutations to disrupt the native secondary structure and packing in the hydrophobic core were discovered to be significant. Query access to the database is available freely on the World Wide Web at http://www.bioinformatics.leeds.ac.uk/group/online/fibril_one.     

GALT Protein Database, a Bioinformatics Resource for the Management and Analysis of Structural Features of a Galactosemia-related Protein and Its Mutants

We describe the GALT-Prot database and its related web-based application that have been developed to collect information about the structural and functional effects of mutations on the human enzyme galactose-1-phosphate uridyltransferase (GALT) involved in the genetic disease named galactosemia type Ⅰ. Besides a list of missense mutations at gene and protein sequence levels, GALT-Prot reports the analysis results of mutant GALT structures. In addition to the structural information about the wild-type enzyme, the database also includes structures of over 100 single point mutants simulated by means of a computational procedure, and the analysis to each mutant was made with several bioinformatics programs in order to investigate the effect of the mutations. The web-based interface allows querying of the database, and several links are also provided in order to guarantee a high integration with other resources already present on the web. Moreover, the architecture of the database and the web application is flexible and can be easily adapted to store data related to other proteins with point mutations. GALT-Prot is freely available at http://bioinformatica.isa.cnr.it/GALT/.     

“十一五”863计划“纳米生物材料研发”重点项目课题布局及实施情况分析

简要分析了"十一五"期间国家高技术研究发展计划(863计划)"纳米生物材料研发"重点项目的课题设置及实施情况。分别从本重点项目研究方向及课题设置、课题承担单位及研究人员结构、课题完成情况及所取得的代表性研究成果等方面进行了具体分析和归纳总结,供广大科技工作者参考。     

十一五863计划"生物信息和生物计算技术"专题课题布局及实施情况分析

简要分析了"十一五"期间国家高技术研究发展计划(863计划)"生物信息和生物计算技术"专题的课题设置及实施情况。分别从本专题研究方向及课题设置、课题承担单位及研究人员结构、课题完成情况及所取得的代表性研究成果等方面进行了具体分析和归纳总结,供广大科技工作者参考。     

十一五国家高技术研究发展计划“重大疾病的分子分型和个体化诊疗”重大项目布局及实施情况分析

简要分析了"十一五"期间国家高技术研究发展计划("863"计划)"重大疾病的分子分型和个体化诊疗"重大项目的课题设置及实施情况。分别从本项目研究方向及课题设置、课题承担单位及研究人员结构、课题完成情况及所取得的代表性研究成果等方面进行了具体分析和归纳总结,供广大科技工作者参考。     

Estimation of random regression parameters

The problem of the best linear unbiased estimation (BLUE) of random regression parameters is considered. It is proved that increasing informations about the mean value of the parameters both extend the class of estimable linear functionals and improve on the estimation. In all investigated cases the uniqueness of BLUE is proved. In the case of known mean values the BLUE is shown to be numerically equivalent with the MMSEE almost everywhere. A numerical example shows the improvements of BLUE due to increasing informations about the mean values of the parameters.     

NRMD: Nuclear Receptor Mutation Database

The NRMD is a database for nuclear receptor mutation information. It includes mutation information from SWISS-PROT/TrEMBL, several web-based mutation data resources, and data extracted from the literature in a fully automatic manner. Because it is also possible to add mutations manually, a hundred mutations were added for completeness. At present, the NRMD contains information about 893 mutations in 54 nuclear receptors. A common numbering scheme for all nuclear receptors eases the use of the information for many kinds of studies. The NRMD is freely available to academia and industry as a stand-alone version at: www.receptors.org/NR/.     

p53 gene mutation: software and database.

A large number of different mutations in the p53 tumor suppressor gene have been identified in all types of cancer. As of October, 1997, this database (http:// perso.curie.fr/tsoussi ) contained >7500 mutations. Such a substantial increase since our previous reports should enable epidemiological analyses which were not previously possible. In order to analyse these new data, the UMD software has been improved. A new Web version of the UMD software enables online analysis of the database. The present report describes various improvements since the last release of the database.     

"十一五"863计划"基于功能基因组和结构基因组的药物分子设计"重点项目课题布局及实施情况分析

简要对 "十一五"期间国家高技术研究发展计划("863"计划)"基于功能基因组和结构基因组的药物分子设计"重点项目的研究方向及课题设置、课题承担单位及研究人员结构、课题完成情况及所取得的代表性研究成果等方面进行了具体分析和归纳总结,供广大科技工作者参考。     

p53 gene mutation: software and database.

A large number of different mutations in the tumor suppressor gene p53 gene have been identified in all types of cancer. As of September 1995, this database contains over 4200 mutations. This substantial increase since our previous report can enable epidemiological analyses which were not previously possible. In order to capture all these new data, the software permitting analysis has been improved. This report describes the various improvements since first release of the database.     

The Human PAX6 Mutation Database.

The Human PAX6 Mutation Database contains details of 94 mutations of the PAX6 gene. A Microsoft Access program is used by the Curator to store, update and search the database entries. Mutations can be entered directly by the Curator, or imported from submissions made via the World Wide Web. The PAX6 Mutation Database web page at URL http://www.hgu.mrc.ac.uk/Softdata/PAX6/ provides information about PAX6, as well as a fill-in form through which new mutations can be submitted to the Curator. A search facility allows remote users to query the database. A plain text format file of the data can be downloaded via the World Wide Web. The Curation program contains prior knowledge of the genetic code and of the PAX6 gene including cDNA sequence, location of intron/exon boundaries, and protein domains, so that the minimum of information need be provided by the submitter or Curator.     

BTKbase, mutation database for X-linked agammaglobulinemia (XLA)

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 368 entries from 318 unrelated families showing 228 unique molecular events. In addition to mutations the database lists also some polymorphisms and site-directed mutations. Each patient is given a unique patient identity number (PIN). Information is provided regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites forming arginine residues. These hot spots have generally pyrimidines 5'and purines 3'to the mutated cytosine. A decreased frequency of missense mutations was found in the TH, SH3 and the upper lobe of the kinase domain. The putative structural implications of all the missense mutations are given in the database showing 228 unique molecular events, including a novel missense mutation causing an R28C substitution as previously seen in the Xid mouse.     

BTKbase, mutation database for X-linked agammaglobulinemia (XLA).

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 225 entries from 189 unrelated families showing 148 unique molecular events. Each patient is given a unique patient identity number (PIN). Information is included regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites forming arginine residues. A decreased frequency of missense mutations was found in the TH, SH3 and upper lobe of the kinase domain. The putative structural implications of all the missense mutations are given in the database.     

BTKbase, mutation database for X-linked agammaglobulinemia (XLA).

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 463 mutation entries from 406 unrelated families showing 303 unique molecular events. In addition to mutations, the database also lists variants or polymorphisms. Each patient is given a unique patient identity number (PIN). Information is included regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites that code for arginine residues. The putative structural implications of all the missense mutations are given in the database. The improved version of the registry having a number of new features is available at http://www. helsinki.fi/science/signal/btkbase.html     

Racial differences in MLH1 and MSH2 mutation: an analysis of yellow race and white race based on the InSiGHT database

MLH1 and MSH2 mutations underlie 90% of hereditary nonpolyposis colorectal cancer (HNPCC) mutations. The International Society of Gastrointestinal Hereditary Tumors (InSiGHT) has established an international database of mutations associated with HNPCC. Based on the InSiGHT database and the original references that reported the mutations, we analyzed the distributions of MLH1 and MSH2 mutations in yellow race and white race respectively and compared them subsequently. We found: (1) the distributions of mutation individuals in exon 1, 17 and 19 of MLH1 gene and in exon 2 of MSH2 gene showed significant differences between the two race groups (p < 0.05); (2) the distributions of mutation types in exon 2, 7 and 18 of MLH1 and exon 10 and 16 of MSH2 showed significant differences (p < 0.05); and (3) three mutations (c.649C > T, c.1625A > T and c.1721T > C) in MLH1 and five mutations (c.23C > T, c.187dupG, c.505A > G, c.1168C > T and c.2211-6T > C) in MSH2 have much higher frequency in yellow race than those in white race. Furthermore, three mutations (c.1453G > C, c.1742C > T and c.1758dupC) in MLH1 and two mutations (c.1255C > A and c.1886A > G) in MSH2 were only found in yellow race, which implies that specific mutations in yellow race need more attention when screening mutations in these two genes.