Biomedical subjects

P M Nowacki

Publications and source records attributed to P M Nowacki.

7 recordsLinked to original sources

PubMed2000

Guidelines and recommendations for content, structure, and deployment of mutation databases: II. Journey in progress.

The HUGO Mutation Database Initiative has produced guidelines and recommendations addressing uniform nomenclature of (human) genes and alleles, and computing standards to permit a moderate level of built-in redundancy, searchable interfaces, and compatibility between the comprehensive (genomic) and locus-specific types of databases. The participating community (developers and users) have been moving the project along rapidly, as described here.

Databases, Factual↗

PubMed2000

PAHdb: a locus-specific knowledgebase.

PAHdb is an online relational locus-specific "mutation database" (http://www.mcgill.ca/pahdb) for the human phenylalanine hydroxylase gene (symbol PAH) and its associated phenotypes (protein, metabolic, clinical). When combined with associated information (population distribution of allele, haplotype association, etc.) PAHdb functions as a knowledgebase. From the outset, and in the absence of raw data (e.g., sequence gels), PAHdb has instead been an annotated repository of information about mutations maintained by a team of curators. It is also disease-oriented, being focused on a variant phenotype (hyperphenylalaninemia (HPA) and its most important form of disease, phenylketonuria (PKU)) resulting from primary dysfunction of the PAH enzyme (EC 1.14.16.1); it is "patient friendly" in that it contains information for those personally involved with HPA/PKU (MIM# 261600). PAHdb also serves its community through direct interaction.

Alleles↗

PubMed1999

Guidelines and recommendations for content, structure, and deployment of mutation databases.

These Guidelines recognize the need for annotated online mutation databases documenting allelic variation (both pathogenic and phenotype modifying, and also neutral polymorphic); the databases will be both generalized (genomic) and specialized (locus specific), and a seamless integration of the two types is intended. Each requires a Document (its "biography"). Different mutation databases will have different content and structure, but a minimum core of content in a shared syntax is a necessity; the core includes: (1) a unique identifier of the allele; (2) the source/report of the data; (3) context of the allele; and (4) the allele itself (the description). The allele description should be validated. There is no single correct way to design a mutation database. The uses to which databases are put dictate the design. Software and deployment together recognize the different needs of specialized and generalized databases, while making them mutually compatible through shared content and the appropriate search facilities. A set of eight Recommendations completes these Guidelines for Content, Design, and Deployment of Mutation Databases.

Alleles↗

PubMed1999

Genomics, mutations and the Internet: the naming and use of parts.

Mutations are the source of genetic variation and diversity; by their effect, some are neutral, others are pathogenic. In contemporary genetics, mutations appear at the interface between genomics (structural and functional) and genetics (heredity), where they serve gene discovery and mapping (genomics) and generate challenges to modify their phenotypic effects (medical genetics). Assuming the human genome harbours 80,000 transcribed genes each possessing at least 100 different (germline) alleles in a typical population, how then to record and recover data on at least 8 million human alleles? Bioinformatics is the essential resource to create the corresponding accessible digital libraries (genomic and locus-specific mutation databases) for this purpose, a goal to which The HUGO Mutation Database Initiative (Science 279: 10-11, 1998) aspires. Guidelines now exist for naming alleles (Hum Mutat 11: 1-3, 1998). The principles behind the practice are illustrated by PAHdb (http:/(/)www.mcgill.ca/ pahdb), a prototype locus-specific mutation database (NAR 26: 220-225, 1998), and by prototype genomic mutation databases (HGMD (NAR 26: 285-287, 1998), http:/(/)www.uwcm.ac.uk/uwcm/mg/hgmd0.h tml; the EBI mutation database, http:/(/)www2.ebi.ac.uk/mutations/; and OMIM, http:/(/)www.ncbi.nlm. nih.gov/Omim.html).

Databases, Factual↗

PubMed1998

PAH Mutation Analysis Consortium Database: 1997. Prototype for relational locus-specific mutation databases.

PAHdb (http://www.mcgill.ca/pahdb ) is a curated relational database (Fig. 1) of nucleotide variation in the human PAH cDNA (GenBank U49897). Among 328 different mutations by state (Fig. 2) the majority are rare mutations causing hyperphenylalaninemia (HPA) (OMIM 261600), the remainder are polymorphic variants without apparent effect on phenotype. PAHdb modules contain mutations, polymorphic haplotypes, genotype-phenotype correlations, expression analysis, sources of information and the reference sequence; the database also contains pages of clinical information and data on three ENU mouse orthologues of human HPA. Only six different mutations account for 60% of human HPA chromosomes worldwide, mutations stratify by population and geographic region, and the Oriental and Caucasian mutation sets are different (Fig. 3). PAHdb provides curated electronic publication and one third of its incoming reports are direct submissions. Each different mutation receives a systematic (nucleotide) name and a unique identifier (UID). Data are accessed both by a Newsletter and a search engine on the website; integrity of the database is ensured by keeping the curated template offline. There have been >6500 online interrogations of the website.

Animals↗

PubMed1998

Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience.

We describe variation at the PAH locus in the population of Quebec. We successfully analyzed 135 of 141 chromosomes from phenylketonuria (PKU) probands (95.7% of the sample), and eight additional chromosomes from a small number of probands with non-PKU hyperphenylalaninemia (HPA). The full set of chromosomes harboured 45 different PAH mutations: i) seven polymorphisms (IVS2nt19, IVS3nt-22, IVS6nt-55, Q232Q, V245V, L385L, Y414Y); ii) four mutations causing non-PKU HPA (T92I, E390G, R408Q, D415N); iii) 34 mutations causing PKU. Only six mutations (M1V, R261Q, F299C, S349P, R408W and IVS12nt1) occurred in the whole province at relative frequencies > 5%: most are rare and probably identical by descent. By studying associations of mutations with polymorphic haplotype alleles, we found examples of mutations on different haplotypes that were identical by state, but not by descent because they were recurrent mutations (E280K and R408W); and examples of mutations identical both by state and by descent because of intragenic recombination (S67P, G218V, V245A and IVS12nt1). Ten mutations were first described in Quebec and five are still unique there; three of these 'Quebec' mutations are reported here for the first time (c.125A-->T (K42I); [c.470G-->A; c.471A--C] (R157N); c.707nt-55 (IVS6nt-55). The PAH mutations stratify by geographic region and population, their distributions validating hypotheses about European range expansion to North America during three separate phases of immigration and demographic expansion in the Quebec region over the past four centuries. The PAH homozygosity value (j) is 0.06 for the total Quebec sample (0.5-0.08 by regions), and the corresponding homoallelic fraction of mutant PAH genotypes is 24%. These findings are a documentation of genetic diversity in the Quebec population.

Alleles↗

PubMed1996

Inflammation and metastases.

Results of experimental studies on cancer dissemination, as well as certain clinical observations, strongly suggest a relation between inflammation and tumor spread. Surgical trauma and postoperative septic complications can result in severe inflammation and in consequence worsening prognosis after curative surgery for colorectal cancer. Clinical signs of inflammation, such as fever, elevated leucocytosis and/or C-reactive protein seem to be of poor prognostic significance, heralding recurrence of cancer. If so, it could be hypothesized that non-steroidal anti-inflammatory drugs may play a beneficial role in reduction of cancer relapses. To evaluate the above hypothesis, non-steroidal anti-inflammatory drugs are suggested as an adjuvant postoperative treatment in a clinical trial on humans.

Animals↗