TY - JOUR
T1 - Molecular characterization of CTNS deletions in nephropathic cystinosis
T2 - Development of a PCR-based detection assay
AU - Forestier, Lionel
AU - Jean, Geneviève
AU - Attard, Marlene
AU - Cherqui, Stéphanie
AU - Lewis, Cathryn
AU - Van't Hoff, William
AU - Broyer, Michel
AU - Town, Margaret
AU - Antignac, Corinne
N1 - Funding Information:
We thank the patients, the families, and the physicians who have contributed to this project. We also thank Viki Kalatzis for helpful discussion and Sheila Fisher for assistance with statistical analysis. This study was supported, in France, by the association Vaincre les Maladies Lysosomales, INSERM (program APEX), and by the Association pour l'Utilisation du Rein Artificiel, and, in the U.K., by the Medical Research Council, the National Kidney Research Fund, and the Kidney Research Aid Fund.
PY - 1999
Y1 - 1999
N2 - Nephropathic cystinosis is an autosomal recessive disorder that is characterized by accumulation of intralysosomal cystine and is caused by a defect in the transport of cystine across the lysosomal membrane. Using a positional cloning strategy, we recently cloned the causative gene, CTNS, and identified pathogenic mutations, including deletions, that span the cystinosis locus. Two types of deletions were detected-one of 9.5-16 kb, which was seen in a single family, and one of ~65 kb, which is the most frequent mutation found in the homozygous state in nearly one-third of cystinotic individuals. We present here characterization of the deletion breakpoints and demonstrate that, although both deletions occur in regions of repetitive sequences, they are the result of nonhomologous recombination. This type of mechanism suggests that the ~65-kb deletion is not a recurrent mutation, and our results confirm that it is identical in all patients. Haplotype analysis shows that this large deletion is due to a founder effect that occurred in a white individual and that probably arose in the middle of the first millenium. We also describe a rapid PCR-based assay that will accurately detect both homozygous and heterozygous deletions, and we use it to show that the ~65-kb deletion is present in either the homozygous or the heterozygous state in 76% of cystinotic patients of European origin.
AB - Nephropathic cystinosis is an autosomal recessive disorder that is characterized by accumulation of intralysosomal cystine and is caused by a defect in the transport of cystine across the lysosomal membrane. Using a positional cloning strategy, we recently cloned the causative gene, CTNS, and identified pathogenic mutations, including deletions, that span the cystinosis locus. Two types of deletions were detected-one of 9.5-16 kb, which was seen in a single family, and one of ~65 kb, which is the most frequent mutation found in the homozygous state in nearly one-third of cystinotic individuals. We present here characterization of the deletion breakpoints and demonstrate that, although both deletions occur in regions of repetitive sequences, they are the result of nonhomologous recombination. This type of mechanism suggests that the ~65-kb deletion is not a recurrent mutation, and our results confirm that it is identical in all patients. Haplotype analysis shows that this large deletion is due to a founder effect that occurred in a white individual and that probably arose in the middle of the first millenium. We also describe a rapid PCR-based assay that will accurately detect both homozygous and heterozygous deletions, and we use it to show that the ~65-kb deletion is present in either the homozygous or the heterozygous state in 76% of cystinotic patients of European origin.
UR - https://www.scopus.com/pages/publications/0033364964
U2 - 10.1086/302509
DO - 10.1086/302509
M3 - Article
C2 - 10417278
AN - SCOPUS:0033364964
SN - 0002-9297
VL - 65
SP - 353
EP - 359
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -