The molecular basis of phenylalanine hydroxylase deficiency in Croatia

Abstract

We present the results of a comprehensive analysis of mutations, polymorphisms and haplotypes in the phenylalanine hydroxylase ( PAH) gene in 39 Croatian families with phenylketonuria (PKU). A total of 21 disease-causing mutations was identified on 78 out of 79 independent chromosomes. The commonest mutation, R408W on haplotype 2 was found with a relative frequency of 37 %. P281L accounted for 11 %, R261Q and E390G each for 9 % of mutant chromosomes. There were three novel mutations: L249P (c.746T>C) in exon 7, IVS8+2T>C (c.912T>C) in intron 8, and F402L (c.1206T>G) in exon 12 of the PAH gene. Two known PKU mutations were found in cis on the same chromosome in one family, highlighting the need to perform full mutation scanning in recessive disease genes for molecular diagnosis even if two known mutations have been identified in a patient. This is the first comprehensive report on PKU mutations in southeastern Europe, adding to the growing bulk of molecular data for population genetic investigations.

Phenylalanine hydroxylase deficiency in south Italy: Genotype–phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness

“…The mutation detection rate is 100%, at the upper limit of the reports from different populations throughout the world (90-99%) [10][11][12]. The mutational spectrum involves 33 mutations, one of which has not previously been identified.…”

Phenylketonuria mutations in Europe

“…In Croatia, R408W-H2 is not quite as common as in eastern European countries, and there are relatively high frequencies of mutations P281L and R261Q. E390G is a common mild mutation in this population [Baric et al, 1992;Zschocke et al, 2003]. There is a remarkably high relative frequency of mutation IVS10-11G4A in Bulgaria [Kalaydjieva et al, 1993].…”

Mutational Spectrum of Phenylketonuria in the Chinese Han Population: A Novel Insight into the Geographic Distribution of the Common Mutations

“…So far, Ͼ500 different mutant alleles have been identified at the PAH locus and listed in the PAH Mutation Analysis Consortium database (http://www.pahdb.mcgill.ca/), which cause different levels of reduction in the catalytic activity of the enzyme, generating a wide spectrum of biochemical and clinical phenotypes (1,2). Data (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) on the distribution and relative frequencies of the mutations have been described for various populations and have shown great variability in the mutational spectrum and differences in the degree of heterogeneity, which are useful for further understanding of both the clinical features and the population genetics of the disorder.…”