GM00046

GM00046 Fibroblast

Description:

CYSTINOSIS, NEPHROPATHIC; CTNS
CYSTINOSIN; CTNS

Affected:

Yes

Sex:

Male

Age:

3 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Amino Acid Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Increased intracellular cystine in fibroblasts; donor subject is hemizygous for a 5-bp deletion at nucleotide 545 in exon 5 of the CTNS gene [545delTCCTT] resulting in a substitution of arginine for isoleucine at codon 69 [Ile69Arg (I69R)] which causes a termination at codon 73; results from targeted next generation sequencing using human genome version hg19 and confirmation by Sanger sequencing indicate that donor subject is hemizygous for mutations in the CTNS gene, allele 1: p.I69Rfs*5/c.206_210delTCCTT, allele 2: 57 kb deletion (exons 1-10), Zykovich et al. Molecular Genetics and Metabolism Reports 5 (2015) 63-66.

Characterizations

Passage Frozen

Gene

CTNS

Chromosomal Location

17p13

Allelic Variant 1

606272.0010; CYSTINOSIS, NEPHROPATHIC

Identified Mutation

5-BP DEL, NT545; Shotelersuk et al. (1998) identified a 5-bp deletion starting at nucleotide 545 resulting in an I69R amino acid substitution and a stop codon at position 73 of the CTNS gene in a patient with classic cystinosis (219800).

Gene

CTNS

Chromosomal Location

17p13

Allelic Variant 2

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.

Phenotypic Data

Remarks

Publications

Zykovich A, Kinkade R, Royal G, Zankel T, Molecular genetics and metabolism reports5:63-66 2015

PubMed ID: 28649545

Vitvitsky, V., Witcher, M., Banerjee, R., and Thoene, J., The redox status of cystinotic fibroblasts Mol Genet Metabol99(2010):384-388 2010

PubMed ID: 20061170

Helip-Wooley A, Park MA, Lemons RM, Thoene JG, Expression of CTNS alleles: subcellular localization and aminoglycoside correction in vitro. Mol Genet Metab75(2):128-33 2002

PubMed ID: 11855931

Park M, Helip-Wooley A, Thoene J, Lysosomal cystine storage augments apoptosis in cultured human fibroblasts and renal tubular epithelial cells. J Am Soc Nephrol13(12):2878-87 2002

PubMed ID: 12444206

Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA, CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet63(5):1352-62 1998

PubMed ID: 9792862

Pentchev PG, Comly ME, Kruth HS, Patel S, Proestel M, Weintroub H, The cholesterol storage disorder of the mutant BALB/c mouse. A primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease. J Biol Chem261:2772-7 1986

PubMed ID: 3949747