Description:
PHENYLKETONURIA
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases |
| Class |
Disorders of Amino Acid Metabolism |
| Quantity |
25 µg |
| Quantitation Method |
Please see our FAQ |
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Biopsy Source
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Peripheral vein
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Cell Type
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B-Lymphocyte
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Tissue Type
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Blood
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Transformant
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Epstein-Barr Virus
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Sample Source
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DNA from LCL
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Race
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White
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Family Member
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3
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Relation to Proband
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brother
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Confirmation
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Clinical summary/Case history
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis |
| |
| Gene |
PAH |
| Chromosomal Location |
12q24.1 |
| Allelic Variant 1 |
261600.0017; HYPERPHENYLALANINEMIA, NON-PKU |
| Identified Mutation |
TYR414CYS (c. 1241A>G); This mutation in exon 12 was found on haplotype 4 in a Caucasian patient (Okano et al., 1991). An A-to-G transition at the second base of codon 414 was responsible. In vitro expression studies showed that the tyr414-to-cys mutation produced a protein with a significant amount of PAH enzyme activity, i.e., approximately 50% of normal steady-state levels.
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| Gene |
PAH |
| Chromosomal Location |
12q24.1 |
| Allelic Variant 2 |
261600.0001; PHENYLKETONURIA |
| Identified Mutation |
IVS12DS, G>A, +1 (c.1315+1 G>A); The first PKU mutation identified in the PAH gene was a single base change (GT-to-AT) in the canonical 5-prime splice donor site of intron 12 (DiLella et al., 1986). Direct hybridization analysis using specific oligonucleotide probes demonstrated tight association with a specific RFLP haplotype called haplotype 3. The splicing mutation was the most prevalent PKU allele among Caucasians. Marvit et al. (1987) found that the GT-to-AT substitution at the 5-prime splice donor site of intron 12 resulted in the skipping of the preceding exon during RNA splicing. cDNA clones had shown an internal 116-basepair deletion corresponding precisely to exon 12 and leading to the synthesis of the truncated protein lacking the C-terminal 52 amino acids. Gene transfer and expression studies using the mutant PAH cDNA indicated that the deletion abolished PAH activity in the cell as a result of protein instability. The studies of Marvit et al. (1987) indicated that in fact a single nucleotide substitution rather than a deletion was the basis of the abnormal gene product.
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| Remarks |
Clinically affected; on dietary therapy; hyperphenylalaninemia; donor subject is a compound heterozygote: one allele has a A>G transition at nucleotide 1241 in exon 12 of the PAH gene [c.1241A>G] resulting in a pathogenic substitution of cysteine for tyrosine at codon 414 [p.Tyr414Cys (p.Y414C)] and a second allele has a pathogenic splice site mutation at nucleotide 1315, c.1315+1G>A [IVS12+1G>A]. |
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