NA02894
DNA from Fibroblast
Description:
CYSTINOSIS, NEPHROPATHIC; CTNS
CYSTINOSIN; CTNS
|
Repository
|
NIGMS Human Genetic Cell Repository
|
| Subcollection |
Heritable Diseases
Lysosomal Storage Diseases |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
|
Cell Type
|
Fibroblast
|
|
Transformant
|
Simian Virus 40
|
|
Sample Source
|
DNA from Fibroblast
|
|
Relation to Proband
|
proband
|
|
Confirmation
|
Clinical summary/Case history
|
|
Species
|
Homo sapiens
|
|
Common Name
|
Human
|
|
Remarks
|
|
| Passage Frozen |
47 |
| |
| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase 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 |
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. |
| Remarks |
SV40 transformed culture, aneuploid; accumulates large amounts of intracellular nonprotein cystine; during subculture, quickly rinse in 0.53mM EDTA and incubate less than 2 minutes in 0.04% trypsin; donor subject is homozygous for a 57-kb deletion (also reported as a 65-kb del) in the CTNS gene that removes the first 10 exons [57-kb del]. |
| La Cognata V, Cavallaro S, Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases Biomedicines10: 2022 |
| PubMed ID: 36009380 |
| |
| 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 |
| |
| 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 |
| |
| Lemons RM, Thoene JG, Mediated calcium transport by isolated human fibroblast lysosomes. J Biol Chem266:14378-82 1991 |
| PubMed ID: 1830585 |
| |
| Baldwin GC, Gasson JC, Kaufman SE, Quan SG, Williams RE, Avalos BR, Gazdar AF, Golde DW, DiPersio JF, Nonhematopoietic tumor cells express functional GM-CSF receptors. Blood73:1033-7 1989 |
| PubMed ID: 2537665 |
| |
| Oshima RG, Pellett OL, Robb JA, Schneider JA, Transformation of human cystinotic fibroblasts by SV40: characteristics of transformed cells with limited and unlimited growth potential. J Cell Physiol93:129-36 1977 |
| PubMed ID: 198418 |
|
|