Phenylketonuria splice mutation (EXON6nt-96Ag) masquerading as missense mutation (Y204C)

Ellingsen, Ståle; Knappskog, Per M.; Eiken, Hans Geir

doi:10.1002/(sici)1098-1004(1997)9:1<88::aid-humu21>3.0.co;2-k

Cited by 30 publications

(22 citation statements)

References 17 publications

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“…This A-to-G transition is a splicing mutation for the disappearance of the consensus sequence of a 5¢ donor splice site instead of a tyrosine to cysteine substitution of codon 204 in exon 6 and would give a 96 bp deletion. 35,36 The most frequent mutations in the Taiwanese population were R241C (32%) and R408Q (14%), each associated with a mild clinical phenotype. Private mutations, which are those seen in Genotypes and BH 4 responsiveness in PKU Y Okano et al one or two alleles, differed among countries, suggesting a relatively recent origin.…”

Section: Comparison Among East Asian Countriesmentioning

confidence: 99%

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

et al. 2011

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Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g4a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH 4 ) responsiveness. The frequency of BH 4 responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH 4 therapy, and genetic counseling in East Asia.

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Section: Comparison Among East Asian Countriesmentioning

confidence: 99%

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

et al. 2011

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“…RT-PCR analysis of illegitimate transcripts, however, revealed the creation of a novel splice site by this allele causing loss of protein function. The mutation was therefore given a new trivial name: E6nt-96A>G [Ellingsen et al, 1997]. Several alleles, including Q304Q (c.912G>A) [Guldberg et al, 1996], T323T (c.969A>G), K398K (c.1194A>G) , and V399V (c.1197A>T) [Chao et al, 2001], initially called silent, are either shown to, or are likely to, promote exon skipping.…”

Section: Expectations Confoundedmentioning

confidence: 99%

PAHdb 2003: What a locus-specific knowledgebase can do

et al. 2003

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For the PKU Special IssuePAHdb, 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 diseasecausing) 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.

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“…34 Similarly, mutations G272X, P281L and R408Q result in transcripts with one or more exons skipped in addition to full-length transcripts, while Y356X yields no full-length transcripts in patients' lymphocytes. 28 This indicates that many mutations believed to affect the PAH enzyme may (also) affect splicing, and consequently patient mRNA should be analysed for all mutations.…”

Section: Proteins With Truncations and Large Deletionsmentioning

confidence: 99%

“…34 The affected region forms part of the dimer interface and would be expected to affect folding, stability and the integrity of the active site.…”

Section: Proteins With Truncations and Large Deletionsmentioning

confidence: 99%

Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype–phenotype correlations in phenylketonuria

Jennings

Cotton²,

Kobe

2000

Eur J Hum Genet

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Phenylalanine hydroxylase (PAH) is the enzyme that converts phenylalanine to tyrosine as a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. Over 300 mutations have been identified in the gene encoding PAH that result in a deficient enzyme activity and lead to the disorders hyperphenylalaninaemia and phenylketonuria. The determination of the crystal structure of PAH now allows the determination of the structural basis of mutations resulting in PAH deficiency. We present an analysis of the structural basis of 120 mutations with a 'classified' biochemical phenotype and/or available in vitro expression data. We find that the mutations can be grouped into five structural categories, based on the distinct expected structural and functional effects of the mutations in each category. Missense mutations and small amino acid deletions are found in three categories: 'active site mutations', 'dimer interface mutations', and 'domain structure mutations'. Nonsense mutations and splicing mutations form the category of 'proteins with truncations and large deletions'. The final category, 'fusion proteins', is caused by frameshift mutations. We show that the structural information helps formulate some rules that will help predict the likely effects of unclassified and newly discovered mutations: proteins with truncations and large deletions, fusion proteins and active site mutations generally cause severe phenotypes; domain structure mutations and dimer interface mutations spread over a range of phenotypes, but domain structure mutations in the catalytic domain are more likely to be severe than domain structure mutations in the regulatory domain or dimer interface mutations. European Journal of Human Genetics (2000) 8, 683-696.

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Phenylketonuria splice mutation (EXON6nt-96Ag) masquerading as missense mutation (Y204C)

Cited by 30 publications

References 17 publications

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

PAHdb 2003: What a locus-specific knowledgebase can do

Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype–phenotype correlations in phenylketonuria

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