The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion
| Autor: | Geraldine McDowell, Stephen M. Beckstrom-Sternberg, William A. Gahl, Nicole Dietrich, Vorasuk Shotelersuk, Gerard G. Bouffard, Jeffrey W. Touchman, Yair Anikster, Valerie Maduro, Eric D. Green |
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| Rok vydání: | 2000 |
| Předmět: |
Lysosomal transport
Positional cloning Cystinosis Molecular Sequence Data Biology medicine.disease_cause Jurkat Cells Nephropathic Cystinosis Report Genetics medicine Lysosomal storage disease Tumor Cells Cultured Animals Humans Cloning Molecular Genetics (clinical) Cells Cultured Glycoproteins Sequence Deletion Mutation Phosphotransferases Chromosome Mapping Membrane Proteins Membrane Transport Proteins Sequence Analysis DNA medicine.disease Physical Chromosome Mapping Molecular biology Rats Transplantation Phosphotransferases (Alcohol Group Acceptor) Amino Acid Transport Systems Neutral Cystinosin Multigene Family Chromosomes Human Pair 17 Transcription Factors |
| Zdroj: | Genome research. 10(2) |
| ISSN: | 1088-9051 |
| Popis: | Nephropathic cystinosis is a rare autosomal recessive, lysosomal storage disease with an incidence estimated at 1 per 100,000–200,000 live births (see http://www.ncbi.nlm.nih.gov/omim; OMIM 219800). The classic disorder is characterized clinically by renal tubular Fanconi syndrome in the first year of life, growth retardation in childhood, renal glomerular failure at ∼10 years of age, hypothyroidism, and a variety of other complications, including photophobia and corneal crystal formation (Gahl 1986; Gahl et al. 1995). After renal transplantation, cystine accumulation continues in nonrenal organs, frequently causing a distal vacuolar myopathy (Charnas et al. 1994), swallowing difficulty (Sonies et al. 1990), or retinal dysfunction (Kaiser-Kupfer et al. 1986), and occasionally causing diabetes mellitus (Fivush et al. 1987), pancreatic exocrine insufficiency (Fivush et al. 1988), or neurological deterioration (Ehrich et al. 1979; Fink et al. 1989). These complications arise because defective lysosomal transport of the disulfide cystine (Gahl et al. 1982a) causes this amino acid to accumulate within the lysosomes of many different cell types, which then triggers cystine crystal formation (Gahl et al. 1982b). The cystine transporter is the first of many lysosomal membrane carriers to be characterized biochemically (Thoene 1992), and cystinosis is the most common of a group of lysosomal transport disorders (Gahl et al. 1995). The gene altered in patients with cystinosis (CTNS) was recently identified by a positional cloning strategy (Town et al. 1998). CTNS is a 12-exon gene that is transcribed into a ∼2.6-kb mRNA. The encoded protein, named cystinosin, consists of a predicted 367 amino acids, appears to be an integral membrane protein, and most likely functions as a cystine transporter. A number of cystinosis-causing CTNS mutations have now been reported (Shotelersuk et al. 1998a; Town et al. 1998). The most prevalent mutation reported to date is a large (>55-kb) deletion, with 33%–44% of affected patients being homozygous for this deletion (Town et al. 1998; Anikster et al. 1999). In addition, at least 11 other smaller disease-causing deletions have been reported (Shotelersuk et al. 1998a; Forestier et al. 1999), suggesting that this genomic region may be prone to rearrangement. We sought to establish the long-range organization of the segment of chromosome 17p13 harboring CTNS and to determine the sequence of this clinically important gene and its surrounding DNA. Here we report the assembly of a detailed bacterial artificial chromosome (BAC)-based physical map encompassing CTNS. In addition, two BAC clones spanning >200 kb were sequenced to high accuracy, providing insight into the molecular architecture of the CTNS gene and the genomic segment commonly deleted in cystinosis patients. |
| Databáze: | OpenAIRE |
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