Hyperphenylalaninemia with High Levels of 7-Biopterin is Associated with Mutations in the PCBD Gene Encoding the Bifunctional Protein Pterin-4a-Carbinolamine Dehydratase and Transcriptional Coactivator (DCoH)
| Autor: | Nenad Blau, Beat Thöny, Pamela Arn, June E. Ayling, Igor Rebrin, L. Kierat, M. Blaskovics, Patrick Ferreira, F. Neuheiser |
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| Jazyk: | angličtina |
| Předmět: |
Male
Phenylalanine DNA Mutational Analysis Mutant Gene Expression Biopterin Biology 7-biopterin 03 medical and health sciences Exon chemistry.chemical_compound 0302 clinical medicine Hyperphenylalaninemia Transcriptional coactivator (DCoH) medicine Genetics Carbinolamine dehydratase (PCD) Humans Genetics(clinical) Child Gene Hydro-Lyases Genetics (clinical) 030304 developmental biology 0303 health sciences Tetrahydrobiopterin Chromosomes Human Pair 10 Infant Newborn Wild type Infant Exons medicine.disease Stop codon chemistry Child Preschool Dehydratase Mutation Female 030217 neurology & neurosurgery Mutations Transcription Factors Research Article |
| Zdroj: | The American Journal of Human Genetics. (6):1302-1311 |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/301887 |
| Popis: | Summary Pterin-4a-carbinolamine dehydratase (PCD) is required for efficient tetrahydrobiopterin regeneration after phenylalanine hydroxylase activity. This catalytic function was proposed to be specifically defective in newborns with a mild form of hyperphenylalaninemia (HPA) and persistent high urinary levels of primapterin (7-biopterin). A second regulatory task of the same protein is DCoH, a coactivation of transcription by hepatocyte nuclear factor 1α (HNF-1α), a function that is apparently not impaired in these HPA individuals. It has been shown elsewhere that the human PCD/DCoH bifunctional protein is encoded by a single 4-exon–containing gene, PCBD , located on chromosome 10q22. We have now examined the PCBD gene for mutations at the genomic level in six such HPA patients from four different families. By the use of new intron-specific primers, we detected, in all six patients, single, homozygous nucleotide alterations, in exon 4, that were inherited from their parents. These homozygous alterations predicted mutant PCD/DCoH with a single amino acid exchange, in two cases (alleles T78I), or premature stop codons, in the other four patients (alleles E86X and Q97X). Recombinant expression in Escherichia coli revealed that the mutant proteins—T78I, E86X, and Q97X—are almost entirely in the insoluble fraction, in contrast to wild type, which is expressed as a soluble protein. These data support the proposal that HPA in combination with urinary primapterin may be due to autosomal recessive inheritance of mutations in the PCBD gene specifically affecting the dehydratase activity. |
| Databáze: | OpenAIRE |
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