Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The R408W mutation in the phenylalanine hydroxylase gene (PAH) of phenylketonuria patients occurs on haplotypes 2.3 and 1.8 in Europeans. The mutation involves a CpG dinucleotide; nonetheless, a single recombination event might also explain the two haplotype associations. By analysis of an STR in the PAH gene 5' to the 408 codon and of the VNTR system in the 3' UTR, we identified unique features of the haplotype 1.8 chromosome harbouring the R408W mutation which are not accounted for by recombination. We conclude that recurrent mutation is the origin of R408W on different PAH haplotypes in Europeans.
Hum Mol Genet 1994 Sep
PMID:Evidence for origin, by recurrent mutation, of the phenylalanine hydroxylase R408W mutation on two haplotypes in European and Quebec populations. 783 27

Taking advantage of the 'illegitimate' transcription of the phenylalanine hydroxylase (PAH) gene, we have been able to analyse the PAH cDNA sequence of hyperphenylalaninemic children in circulating lymphocytes. Using this approach, we have also identified 3 novel mutations in cDNA from liver and lymphocytes of two patients. One mutation, detected by the abnormal pattern of migration of an amplified fragment, is a C to T transition in the splice acceptor site of intron 10, which resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (-3 IVS10). The other two mutations are missense mutations in exons 10 and 11 (respectively, L333F and E390G). The present study supports the view that circulating lymphocytes give easy access to PAH gene transcripts whose nucleotide sequence is identical to that reported in liver and therefore represent a useful tool for molecular genetic studies in phenylketonuria.
Hum Mol Genet 1993 Jan
PMID:Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria. 809 45

Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by phenylalanine hydroxylase (PAH) deficiency. Individuals afflicted with PKU develop irreversible mental retardation that can be largely prevented by the administration of a low-phenylalanine diet. A number of restriction fragment-length polymorphisms (RFLPs) have been identified in the PAH gene. Combinations of RFLPs constitute unique haplotypes that can be used to identify mutant PAH chromosomes for prenatal diagnostic purpose in PKU families. Unfortunately, the utility of haplotype analysis is limited in populations with a single predominant haplotype. We have identified a novel short tandem repeat (STR) within the PAH gene that has an average level of heterozygosity of about 75% in Orientals and about 80% in European Caucasian populations. This single marker is as informative as haplotype analysis in Europeans and nearly twice as informative as haplotype analysis in Orientals. Although there is statistically significant disequilibrium between STR alleles and RFLP-based haplotypes, there is a relatively low degree of disequilibrium between STR alleles and certain RFLP sites. Nevertheless, the combined use of the STR and RFLP haplotype systems increases the informativity of linkage-based tests for prenatal diagnosis and carrier screening in PKU families.
Hum Mol Genet 1993 May
PMID:A single polymorphic STR system in the human phenylalanine hydroxylase gene permits rapid prenatal diagnosis and carrier screening for phenylketonuria. 810 Jan 64

Hyperphenylalaninemia due to a deficiency of hepatic phenylalanine hydroxylase (PAH) is the most common inborn error of amino acid metabolism. Clinically, the disorder is highly heterogeneous, spanning from nonphenylketonuria hyperphenylalaninemia to classical phenylketonuria. Only little is known about the molecular defects underlying hyperphenylalaninemia in Southern Europe. In this study, we conducted a systematic analysis of 53 patients from the Sicilian population. Each patient included in the study had persistently elevated blood levels of phenylalanine and met the differential criteria for PAH deficiency. Genomic DNA was analysed by scanning all PAH-coding exons for mutations by PCR in combination with denaturing gradient gel electrophoresis (DGGE). 52 patients were completely genotyped. A spectrum of 40 different mutations was established including 17 novel PAH mutations. Our results explain the clinical heterogeneity of hyperphenylalaninemia in Southern Europe, and form the basis for the establishment of phenotype-genotype correlations in Sicily and surrounding countries.
Hum Mol Genet 1993 Oct
PMID:Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. 826 25

The amplification refractory mutation system (ARMS) is a powerful technique for the identification of mutations. We present a modification of this technique involving coamplification of normal and mutant alleles with primers that differ in length by three to five bases. Fluorescent labelling allows exact sizing of the amplification products on an automated DNA fragment analyser. We have used the fluorescent multiplex ARMS method for the identification of common phenylketonuria mutations in Northern Ireland (R408W, 165T and F39L) together with the analysis of a polymorphic short tandem repeat site at the human phenylalanine hydroxylase locus. This provides an efficient and inexpensive first step for diagnostic mutation analysis in our population.
Mol Cell Probes 1995 Dec
PMID:A fluorescent multiplex ARMS method for rapid mutation analysis. 880 16

Seventy-two adults with phenylketonuria were evaluated to investigate the genotypic relationship to phenotype. Patient data were collected by chart review and medical follow-up as well as current psychological evaluation. Nineteen diagnosed neonatally had remained on a phenylalanine-restricted diet all their lives, whereas 34 who were also diagnosed on newborn screening had discontinued dietary restriction during childhood. Nineteen others who were born prior to newborn screening were diagnosed later than the newborn period on clinical grounds but have remained on dietary restriction. Comparison between intellectual ability, academic achievement, and mental illness was made with degree of diet control as defined by range of blood phenylalanine levels over time. Diet discontinuation in childhood did not significantly lower IQ per se but appeared to diminish academic achievement. The lowest IQ scores were associated with poor dietary restriction of phenylalanine in the diet during childhood. While there appears to be a strong genotypic relationship to phenotypic metabolic parameters in phenylketonuria, there does not seem to be a similar relationship to intellectual ability in adults. Mutation R408W was not strongly related to the occurrence of mental illness in this sample. We conclude that dietary restriction of phenylalanine neonatally and good control contributed to normal intellectual development. Continuation of dietary treatment into adulthood appeared to improve academic achievement in patients with severe phenylalanine hydroxylase mutations.
Biochem Mol Med 1997 Apr
PMID:The relationship of genotype to phenotype in phenylalanine hydroxylase deficiency. 916 88

Newborn screening for phenylketonuria (PKU) is now the standard of practice. Initial phenylalanine blood levels of 240 mumol/L result in referral of affected newborns to medical facilities experienced in caring for patients with metabolic disorders. This case report concerns a female infant born in 1976 with a presumptive positive PKU screening test on the third day of life of 240 mumol/L phenylalanine. Follow-up levels while the mother was breast feeding on the sixth day of life were 324 and, on the 27th day, 312 mumol/L. She was subsequently lost to follow-up at age 11 years, but returned at 19 years of age due to pregnancy, with a blood phenylalanine level of 132 mumol/L. Mutation studies then were performed documenting that she was a carrier for the phenylalanine hydroxylase gene and did not have hyperphenylalaninemia. The mother's parents and the infant were also genotyped confirming heterozygosity. The infant on follow-up is completely normal, following a normal pregnancy.
Mol Genet Metab 1998 Feb
PMID:Mild hyperphenylalaninemia and heterozygosity of the phenylalanine hydroxylase gene. 956 69

Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.
Mol Med Today 1998 May
PMID:Therapeutic uses of microencapsulated genetically engineered cells. 961 2

A simple, rapid, reliable and convenient method was developed to analyze the gene defects in Phenylketonuria (PKU) and Homocystinuria (HCU). In this method, illegitimately transcribed phenylalanine hydroxylase (PAH) and cystathionine beta-synthase (CBS) mRNAs in peripheral lymphocytes were used as templates for amplification by RT-PCR. The amplified products were confirmed by restriction enzyme digestions, southern blot hybridizations and sequencing. Point mutations in the protein coding region and splice junction mutations of PAH and CBS can be analyzed by this method.
Biochem Mol Biol Int 1998 Jul
PMID:Amplification of phenylalanine hydroxylase and cystathionine beta-synthase transcripts in human peripheral lymphocytes by RT-PCR. 971 86

The potential benefits to society of treating late-diagnosed mentally retarded persons with phenylketonuria were investigated. In order to ascertain the effects of late dietary intervention, the charts of 124 adults with PKU seen in the metabolic service at the Childrens Hospital of Los Angeles were reviewed. Fifty-nine were diagnosed later than 3 months of age and were over the age of 18 years. They were followed up with medical, psychological, and nutritional assessments. Genotyping was also performed. Twenty-eight have remained on a phenylalanine-restricted diet during the intervening years. All but 3 of the 28 late-diagnosed PKU persons who remained on a restricted diet showed significant intellectual improvement. Seven are able to attend college, 9 are employed, and 12 are attending workshops and/or day care programs. The result of treatment with the phenylalanine-restricted diet was that these individuals could participate in society and were able to arrest the neurodegenerative course characteristic of persons with mutations classified as severe in the phenylalanine hydroxylase gene. We conclude that society could benefit substantially by providing a phenylalanine-restricted diet for late-diagnosed mentally retarded persons with phenylketonuria. Eighteen of 28 such persons who otherwise would have required residential care are living independently.
Mol Genet Metab 1999 Jun
PMID:Long-term beneficial effects of the phenylalanine-restricted diet in late-diagnosed individuals with phenylketonuria. 1035 14


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