GM00006

GM00006 Fibroblast

Description:

PHENYLKETONURIA

Affected:

Yes

Sex:

Female

Age:

5 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Amino Acid Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Hyperphenylalaninemia; normal level of dihydropteridine reductase in skin fibroblasts; 46,XX; donor subject is a compound heterozygote: one allele has a C>T transition at nucleotide 842 in exon 7 of the PAH gene [842C>T] resulting in a substitution of leucine for proline at codon 281 [Pro281Leu (P281L)] and a second allele has a G>A transition at nucleotide 1223 in exon 12 of the PAH gene [1223G>A] resulting in a substitution of glutamine for arginine at codon 408 [Arg408Gln (R408Q)].

Characterizations

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

Gene

PAH

Chromosomal Location

12q24.1

Allelic Variant 1

261600.0012; PHENYLKETONURIA

Identified Mutation

PRO281LEU; This mutation in exon 7 was found on haplotype 1 in an Italian patient with PKU (Okano et al., 1991). cDNA carrying the mutation was constructed and transfected into cultured mammalian cells. Expression analysis revealed negligible enzyme activity and undetectable levels of immunoreactive PAH protein. This mutation, like the arg252-to-trp mutation (261600.0007), is in marked linkage disequilibrium with RFLP haplotype 1. The pro281-to-leu mutation was found on 20% of haplotype 1 mutant chromosomes in the Italian population (Okano et al., 1991). Dworniczak et al. (1991) found this mutation on 25% of all mutant haplotype 1 alleles in the German population. In addition, they identified this mutation on 1 mutant haplotype 4 allele. Expression analysis of the mutant allele in cultured mammalian cells demonstrated absence of immunoreactive PAH in cells transfected with this missense mutation, identical steady state levels of mRNA in cells carrying both normal and mutant constructs, and absence of PAH activity in cells transfected with the mutant allele. Baric et al. (1994) pointed to data indicating that the highest frequency of the P281L mutation is in Croatia where it was detected in 55% of haplotype 1 alleles, corresponding to 12% of all PKU alleles. They interpreted this finding as indicating that the mutation originated in southeastern Europe.

Gene

PAH

Chromosomal Location

12q24.1

Allelic Variant 2

261600.0038; PHENYLKETONURIA

Identified Mutation

ARG408GLN; In a Norwegian patient, Eiken et al. (1992) identified a novel mutation in exon 12 in association with haplotype 12 alleles, by use of SSCP analyses. A patient who was homozygous for the R408Q mutation exhibited a mild PKU variant. Eiken et al. (1992) mapped the district of origin of the R408Q and F299C mutations by determining the birthplaces of the relevant grandparents. In contrast to both the overall distribution of PKU mutations and the general population density in Norway, the ancestors of these 2 mutations appeared to be restricted to the western and northern coastal districts. See 261600.0042. In Chinese, Lin et al. (1992) found a G-to-A transition in codon 408 as the basis of phenylketonuria. The missense mutation resulted in the substitution of arginine for glutamine and accounted for about 5% of PKU chromosomes among Chinese. The mutation was in linkage disequilibrium with RFLP haplotype 4. The arg408-to-trp mutation (261600.0002) is in the same codon.

Phenotypic Data

Remarks

Publications

Yeeok Kang, Seong-Hyeuk Nam, Kyung Sun Park, Yoonjung Kim, Jong-Won Kim, Eunjung Lee, Jung Min Ko, Kyung-A Lee and Inho ParkEmail, DeviCNV: detection and visualization of exon-level copy number variants in targeted next-generation sequencing data BMC Bioinformatics19: 2018

PubMed ID: 30326846