Focus on the molecular genetics of phenylketonuria.

Abstract

Phenylketonuria (PKU) has been frequently described as a paradigm of a Mendelian disorder. It was the first metabolic cause of mental retardation to be identified [F lling, 1934], the first genetic disorder of the central nervous system that could be fully treated by modification of external factors (i.e., the diet) [Bickel et al., 1953], and the first disorder that was successfully diagnosed by universal neonatal screening [Guthrie and Susie, 1963]. Twenty years have now passed since the phenylalanine hydroxylase (PAH) gene, mutated in PKU, was identified and the first molecular tests were carried out in PKU families [Woo et al., 1983]. In the pioneering early years, every novel mutation was published as a full research paper and several groups started to examine the molecular basis of PKU in various populations. The correlation between genotypes and phenotypes was investigated [Okano et al., 1991], the molecular basis of mild hyperphenylalaninemia (MHP, the mild form of PAH deficiency that does not require treatment) was elucidated [Economou-Petersen et al., 1992], and the population genetics of PKU was examined [Eisensmith et al., 1992]. Researchers joined to form the PKU Mutation Analysis Consortium and mutations were recorded in the PAH mutation database, one of the first of its kind [Hoang et al., 1996]. Over the last few years, mutation analysis in the PAH gene has developed into a diagnostic service offered by various laboratories on a routine basis in many countries. The manuscripts assembled for this special issue provide an overview of current topics in the molecular genetics of PKU. Human Mutation Co-Editors Richard Cotton and Haig Kazazian, Managing Editor Mark Paalman, and Publisher Wiley-Liss have generously agreed to provide the contents of this special PKU issue online for free access at www.interscience.wiley. com/humanmutation. Scriver et al. [2003] summarize the current structure and content of PAHdb (www.pahdb.mcgill.ca) that has developed from a PKU mutation database into a ‘‘knowledgebase’’ for researchers, clinicians, and lay-persons alike. It covers a wide range of topics related to PKU and the PAH gene. A meta-analysis by Zschocke [2003] of available molecular data from almost all European countries identified 29 different mutations that reach relative allele frequencies of 3% or greater in at least two populations and may be regarded as the common European PKU mutations. Pey et al. [2003] used in vitro expression analysis to elucidate and confirm that some PKU mutations cause severe structural defects, others destroy the catalytic center, and the majority represent folding defects that cause reduced stability and accelerated degradation. Waters [2003] reviews various methods used for expression analysis of PKU mutations and highlights the pathogenetic relevance of PAH protein misfolding caused by the majority of PKU mutations. Gable et al. [2003] report a novel semi-quantitative multiplex-PCR method for the identification of genomic rearrangements in the PAH gene and describe the first duplication identified as a cause of PKU. Tighe et al. [2003] investigated the population genetic relevance of different alleles of the VNTR cassette in the PAH gene with regard to normal chromosomes and the recurrent PKU mutation R408W. Krawczak and Zschocke [2003] continue the discussion on heterozygote advantage in PKU. In order to explain the high frequency of different mutations in independent populations, they argue that an as yet unknown selective mechanism must have played a role in the past. Complete PKU mutation data from several populations are published as Mutations in Brief in this issue. Kasnauskiene et al. [2003] and Pronina et al. [2003] confirm that R408W is by far the most common PKU mutation in Lithuania and Latvia. Croatian patients investigated by Zschocke et al. [2003] include one patient with three distinct missense mutations in the PAH gene. Molecular studies carried out in southern Germany by Aulehla-Scholz and Heilbronner [2003]