NA17885

NA17885 DNA from Fibroblast

Description:

CYSTINOSIS, NEPHROPATHIC; CTNS
CYSTINOSIN; CTNS

Affected:

Yes

Sex:

Female

Age:

9 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Amino Acid Metabolism

Quantity

50 µg

Quantitation Method

Please see our FAQ

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

DNA from Fibroblast

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; photophobia; corneal crystals; renal tubular Fanconi syndrome; proteinuria; glucosuria; generalized aminoaciduria; elevated white blood cell cystine; successful early treatment; similarly affected sister; donor subject is a compound heterozygote: one allele has a 57 kb deletion of exons 1 through 10 of the CTNS gene causing the elimination of expression of the protein and the second allele carries a 1261G>A mutation in exon 11 resulting in a Gly308-to-Arg substitution [Gly308Arg (G308R)]; Zykovich et al. Molecular Genetics and Metabolism Reports 5 (2015) 63-66 confirmed these mutations with targeted next generation sequencing using human genome version hg19 and Sanger sequencing.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase,Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis

Gene

CTNS

Chromosomal Location

17p13

Allelic Variant 1

606272.0005; CYSTINOSIS, NEPHROPATHIC

Identified Mutation

57-KB DEL; This common mutation in nephropathic cystinosis (219800) was originally reported as a 65-kb deletion. Touchman et al. (2000) sequenced 200 kb surrounding the CTNS gene and found that the deletion is approximately 57 rather than 65 kb. The authors identified SHPK (605060), which they designated CARKL, within this deleted region. The findings indicated that the 57-kb deletion includes deletion of CARKL in addition to CTNS, which may account for phenotypic variability in patients. In a French/British report (Town et al., 1998), 23 (33%) of 70 patients with nephropathic cystinosis had a 65-kb deletion in the CTNS gene. Among American-based patients studied by Shotelersuk et al. (1998), 48 (44%) of 108 were homozygous for the 65-kb 'European' deletion. Of 96 alleles from these patients, 82 were assigned a nation of origin; 38 (46%) derived from Germany and 28 (34%) arose from the British Isles. Two apparently unrelated patients with homozygous deletions came from Iceland. In addition to the 48 patients homozygous for the 65-kb deletion, many of the patients may have a single copy of the deletion. An upstream deletion breakpoint needed to be determined before a PCR-based test of heterozygosity for the deletion could be developed. Gahl et al. (2002) stated that the 57-kb deletion is found in the homozygous state in approximately 50% of patients of northern European descent who have cystinosis. This founder mutation, which removes the first 10 exons of CTNS and eliminates expression of the protein, apparently occurred in Germany in approximately 500 A.D. (Shotelersuk et al., 1998) and spread by migration to other regions, including Iceland. Bendavid et al. (2004) described a FISH method permitting cytogenetic laboratories to test for the 57-kb deletion, which is found in approximately 60% of patients with cystinosis in the United States and northern Europe. Wamelink et al. (2008) found that cystinosis patients homozygous for the 57-kb deletion had increased urinary sedoheptulose and erythritol compared to patients with other CTNS mutations. Enzyme studies of cultured fibroblasts revealed an 80% reduction in sedoheptulose phosphorylating activity compared to cystinosis patients with other mutations and controls. The findings indicated that the CARKL gene encodes sedoheptulokinase, which functions in the pentose phosphate pathway. Compound Heterozygosity for the 57-kb Deletion In a 38-year-old woman who presented with photophobia at 38 years of age but had suffered chronic sensitivity to light (219750), Anikster et al. (2000) identified compound heterozygosity for the 57-kb deletion and a 928G-A transition, resulting in a glycine to arginine substitution at codon 197 (G197R; 606272.0011). Compound heterozygosity was also found in 2 additional patients from the same family with ocular cystinosis. In a Spanish patient with juvenile-onset nephropathic cystinosis (219900), Macias-Vidal et al. (2009) identified compound heterozygosity for a 416C-T transition in the CTNS gene, resulting in a ser139-to-phe (S139F; 606272.0018) substitution, and the 57-kb deletion.

Gene

CTNS

Chromosomal Location

17p13

Allelic Variant 2

G308R; CYSTINOSIS, NEPHROPATHIC

Identified Mutation

1261G>A