PAHdb 2003 : what a locus-specific knowledgebase can do?

Department of Biological Sciences, Wichita State University, Wichita, KansasFor the PKU Special IssuePAHdb, a legacy of and resource in genetics, is a relational locus-specific database (http://www.pahdb.mcgill.ca). It records and annotates both pathogenic alleles (n=439, putative disease-causing) and benign alleles (n=41, putative untranslated polymorphisms) at the human phenylalaninehydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) andtheir trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typicalfor mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites areinterconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of theallele (submitter, publication, or population); polymorphic haplotype background; and effect of the alleleas predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.16.1) or byin vitro expression analysis. The majority (63%) of the putative pathogenic PAH alleles are pointmutations causing missense in translation of which few have a primary effect on PAH enzyme kinetics.Most apparently have a secondary effect on its function through misfolding, aggregation, and intracellulardegradation of the protein. Some point mutations create new splice sites. A subset of primary PAHmutations that are tetrahydrobiopterin-responsive is highlighted on a Curators’ Page. A clinical moduledescribes the corresponding human clinical disorders (hyperphenylalaninemia [HPA] and phenylk-etonuria [PKU]), their inheritance, and their treatment. PAHdb contains data on the mouse gene (Pah)and on four orthologous mutant mouse models and their use (for example, in research on oral treatmentof PKU with the enzyme phenylalanine ammonia lyase [EC 4.3.1.5]). Hum Mutat 21:333–344,2003.