Description:
CYSTINOSIS, ADULT NONNEPHROPATHIC
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
Lysosomal Storage Diseases |
| Class |
Disorders of Amino Acid Metabolism |
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Cell Type
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Fibroblast
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Transformant
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Untransformed
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Race
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White
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Family Member
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1
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Relation to Proband
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proband
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Confirmation
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Clinical summary/Case history
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| Passage Frozen |
6 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis |
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| Gene |
CTNS |
| Chromosomal Location |
17p13 |
| Allelic Variant 1 |
606272.0011; CYSTINOSIS, ADULT NONNEPHROPATHIC |
| Identified Mutation |
c.589G>A |
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| Gene |
CTNS |
| Chromosomal Location |
17p13 |
| Allelic Variant 2 |
606272.0005; CYSTINOSIS, ADULT NONNEPHROPATHIC |
| 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 |
Photophobia; cystine crystals in cornea and conjunctiva; white blood cells and fibroblasts show increased cystine concentrations; results from targeted next generation sequencing using human genome version hg19 and confirmation by Sanger sequencing indicate that donor subject is compound heterozygous for mutations in the CTNS gene, allele 1: p.G197R/c.589G>A, allele 2: 57 kb deletion (exons 1-10), Zykovich et al. Molecular Genetics and Metabolism Reports 5 (2015) 63-66. |
| Zykovich A, Kinkade R, Royal G, Zankel T, Molecular genetics and metabolism reports5:63-66 2015 |
| PubMed ID: 28649545 |
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| Park MA, Thoene JG, Potential role of apoptosis in development of the cystinotic phenotype Pediatric nephrology (Berlin, Germany)20:441-6 2004 |
| PubMed ID: 15622500 |
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| 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 |
| Passage Frozen |
6 |
| Split Ratio |
1:3 |
| Temperature |
37 C |
| Percent CO2 |
5% |
| Medium |
Eagle's Minimum Essential Medium with Earle's salts and non-essential amino acids with 2mM L-glutamine or equivalent |
| Serum |
15% fetal bovine serum Not inactivated |
| Substrate |
None specified |
| Subcultivation Method |
trypsin-EDTA |
| Supplement |
- |
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