Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions

Abstract

We present an extensive study of the genetic diversity of phenylalanine hydroxylase deficiency in the Spanish phenylketonuria population. We have analysed 195 PKU patients by DGGE analysis identifying 67 different mutations which represent 89% of the total mutant chromosomes. Seventeen mutations first described in Spain have not yet been detected elsewhere; ten of these are reported here for the first time. The clinical significance of this high genetic heterogeneity was examined by analysing the genotype-phenotype correlations, mainly focusing on the mild hyperphenylalaninaemia (MHP) phenotype. The genotypes found in a group of 93 MHP patients, the largest analysed so far, are described in detail, as well as the relative frequencies of the MHP mutations identified. From the total pool of mutations, 27 can be considered severe, 18 can be defined as mild and 13 as associated with MHP. The prevalent mutations correspond to one severe mutation (IVS10nt-11), one MHP mutation (A403V) and two mild mutations (I65T and V388M). The high frequency of mutations with a low degree of severity can explain the relatively higher prevalence of MHP and mild PKU phenotypes in Spain compared with Northern European populations. We have looked at the geographical distribution in Spain of the more common mutations, finding evidence of local mutation clustering, which could be the result of differences in the ethnic background and/or of genetic drift within each region.

A preliminary mutation analysis of phenylketonuria in southwest Iran

“…This loss of enzymatic function is most likely caused by conformational changes due to the presence of three additional amino acids (Gly-Leu-Gln) between the normal sequences encoded by exon 10 and exon 11 (Dworniczak et al, 1991). This mutation has been identified as the most common mutation in Mediterranean populations such as Turkey (Dobrowolski et al, 2011), Italy (Daniele et al, N. Ajami et al 2007), Spain (Desviat et al, 1999), Egypt (Effat et al, 1999), and Israel (Bercovich et al, 2008). In previous studies that have been performed in Iran, IVS10-11G>A was also identified with the highest frequency (Bonyadi et al, 2010;Zare-Karizi et al, 2011).…”

PAHdb 2003: What a locus-specific knowledgebase can do

“…Expression analysis of PAH mutations also has the potential to shed light on genotype/phenotype relationships [Okano et al, 1991] and, in broad terms, such correlations exist [Kayaalp et al, 1997;Guldberg et al, 1998;Desviat et al, 1999]. There are, however, significant exceptions.…”

Phenylketonuria mutations in Europe

“…Not included in Table 1 is mutation c.165delT, which has a relative allele frequency of 4% in Sicily. There are data for various regions of Spain, but the latest publication does not provide regional allele frequencies for the less common mutations [Desviat et al, 1999], and the national data for these mutations were taken from a previous publication . A separate study examined the PKU mutation frequencies in the eastern region of Catalonia; data from this study were corrected by a factor of 0.9 as apparently the total number of characterized (and not independent) chromosomes was taken as 100% [Mallolas et al, 1999].…”