Charles Scriver: Epitome of the physician scientist.

Charles Scriver is a towering figure in the medical genetics community. At 92 he can look back upon a remarkable career that established the field of biochemical genetics, a subsection of medical genetics that is translating the developments in basic genetics into the diagnoses and treatments of inherited biochemical diseases. This biographical sketch summarizes the key achievements of Dr. Scriver in research and medicine, integrating the different components of medical genetics into comprehensive provincial programs, teaching a generation of physicians and researchers, and developing worldwide collaborations. Charles has been a mighty figure in so many ways. He began his career by bringing amino acid chromatography from London to North America, thereby greatly enlarging the scope of metabolic disorders. Subsequently, his editorship of the classic Metabolic and Molecular Bases of Inherited Disease brought metabolism into genetics and established the field of biochemical genetics. He discovered a number of new diseases and was the first to recognize shared mediated amino acid transporters in the kidney, a medical breakthrough that has become a basic concept of amino acid homeostasis. He led the formation of the Quebec Network of Genetic Medicine, incorporating screening, diagnosis, counseling, treatment and research of genetic diseases, which to this day serves as a model for collaborative and comprehensive medical genetic programs internationally. He initiated the development of sapropterin (Kuvan®), the first non-dietary treatment for phenylketonuria (PKU) and helped identify the mechanism of this cofactor's action on phenylalanine hydroxylase in variants of PKU. His laboratory also led the development of phenylalanine ammonia lyase (Palynziq®), an enzyme substitution therapy that now serves as an alternative to dietary treatment for PKU. The ecosystem that Charles generated at the deBelle laboratory was collegial and highly fruitful. With the input and support of his remarkable wife Zipper, he found a way to integrate the concept of family into his work environment. Bustling with an endless series of evolving activities, he generated an inclusive setting which drew on the talents of brilliant clinical and research staff, as well as the input of patients and their families. In all these efforts, Charles managed to answer his own musings summarized in the following three questions: Who do we serve? How do we serve? Why do we serve? Charles Scriver's life is one well lived. An extraordinary physician scientist whose accomplishments are cause for pause and wonder; generating volumes of contribution which will forever seem impossible for one individual to deliver.

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

PAHdb, 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 phenylalanine hydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) and their trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typical for mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites are interconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of the allele (submitter, publication, or population); polymorphic haplotype background; and effect of the allele as predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.16.1) or by in vitro expression analysis. The majority (63%) of the putative pathogenic PAH alleles are point mutations 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 intracellular degradation of the protein. Some point mutations create new splice sites. A subset of primary PAH mutations that are tetrahydrobiopterin-responsive is highlighted on a Curators' Page. A clinical module describes the corresponding human clinical disorders (hyperphenylalaninemia [HPA] and phenylketonuria [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 treatment of PKU with the enzyme phenylalanine ammonia lyase [EC 4.3.1.5]).