GM01565

GM01565 LCL from B-Lymphocyte

Description:

PHENYLKETONURIA
CYSTATHIONINE GAMMA-LYASE; CTH
CYSTATHIONINURIA

Affected:

Yes

Sex:

Female

Age:

16 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Amino Acid Metabolism

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Family Member

Relation to Proband

proband

Confirmation

Molecular characterization after cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Also has cystathioninuria; donor subject is a compound heterozygote: one allele has a pathogenic G>A transition at nucleotide 755 in exon 7 of the PAH gene [755G>A] resulting in a substitution of glutamine for arginine at codon 252 [Arg252Gln (R252Q)] and a second allele on exon 12 has a pathogenic splice site mutation at nucleotide 1315, c.1315+1G>A [IVS12+1G>A]; HLA type A28,Aw24,B7,Bw35; donor subject is also homozygous for a C>T transition at nucleotide 356 in exon 2 of the CTH gene (356C>T) resulting in the substitution of isoleucine for threonine at codon 67 [Thr67Ile (T67I)]

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

Gene

PAH

Chromosomal Location

12q24.1

Allelic Variant 1

R252Q; PHENYLKETONURIA

Identified Mutation

ARG252GLN

Gene

CTH

Chromosomal Location

1p31.1

Allelic Variant 1

607657.0003; CYSTATHIONINURIA

Identified Mutation

THR67ILE

Gene

CTH

Chromosomal Location

1p31.1

Allelic Variant 2

607657.0003; CYSTATHIONINURIA

Identified Mutation

THR67ILE

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.

Phenotypic Data

Remarks

Publications

Veleva D, Ay M, Ovchinnikov DA, Prowse ABJ, Menezes MJ, Nafisinia M, Generation of two lymphoblastoid-derived induced pluripotent stem cell (iPSC) lines from patients with phenylketonuria Stem cell research77:103407 2024

PubMed ID: 38552357

Wang J, Hegele RA, Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH). Hum Genet112(4):404-8 2003

PubMed ID: 12574942