Mutations of CTNS Causing Intermediate Cystinosis

Thoene, Jess G.; Lemons, Rosemary; Anikster, Yair; Mullet, Jodi; Paelicke, K; Lucero, Cynthia; Gahl, William A.; Schneider, Jerry A.; Shu, San-Ging; Campbell, H T

doi:10.1006/mgme.1999.2876

Cited by 72 publications

(60 citation statements)

References 12 publications

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“…This genotype is consistent with loss of protein function and therefore is compatible with the severe infantile nephropathic phenotype of the patient. Mutations of CTNS splice sites have been described in all three variants of cystinosis with CTNS mutations located in IVS 4,5,7,8,9,10 and 11 (Anikster et al, 1999b;Attard et al, 1999;Kleta et al, 2001;Thoene et al, 1999;Town et al, 1998). The mutation identified in this patient represents the ninth splicing mutation and the first in IVS 3 reported among nephropathic cystinosis patients.…”

Section: Novel Mutations In Patients Of German and Swiss Originmentioning

confidence: 64%

Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis

et al. 2002

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The autosomal recessive lysosomal storage disorder, nephropathic cystinosis is characterized by impaired transport of free cystine out of lysosomes. The gene responsible for cystinosis, CTNS, consists of 12 exons and encodes a 55 kDa putative lysosomal membrane protein, called cystinosin. Up to now more than 55 different CTNS mutations have been described in cystinosis. We have analyzed the mutation pattern in a population of 40 cystinosis patients from 35 families of German and Swiss origin. CTNS mutations in 68 out of 70 alleles were identified. The common 57-kb deletion accounted for 65% of the alleles. In five patients we found a known GACT deletion at position 18-21. In two patients we identified a nucleotide substitution at codon 339 and one patient showed a CG insertion at position 697-698. In five patients we observed a G insertion at position 926-927. Moreover, five novel mutations including two deletions involving exon 3 (61-61+2delGGT) and exon 6 (280delG), two insertions in exon 6 (292-293insA) and exon 7 (684insCACTT) and one nucleotide substitution in exon 11 (923G>T) have been identified. These data provide a basis for routine molecular diagnosis of cystinosis in the central European population, especially in cystinosis patients of German and Swiss origin.

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Section: Novel Mutations In Patients Of German and Swiss Originmentioning

confidence: 64%

Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis

et al. 2002

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“…CTNS mutations were thereafter detected in all forms of the disease, confirming their allelic status (1,2,30,31). CTNS is localized to 17p13 and is composed of 12 exons, with the predicted translation start site situated in exon 3 (31).…”

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confidence: 68%

Intralysosomal Cystine Accumulation in Mice Lacking Cystinosin, the Protein Defective in Cystinosis

Cherqui

Sevin

Hamard

et al. 2002

Molecular and Cellular Biology

149

143

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Cystinosis is an autosomal recessive disorder characterized by an accumulation of intralysosomal cystine. The causative gene, CTNS, encodes cystinosin, a seven-transmembrane-domain protein, which we recently showed to be a lysosomal cystine transporter. The most severe and frequent form of cystinosis, the infantile form, appears around 6 to 12 months, with a proximal tubulopathy (de Toni-Debré-Fanconi syndrome) and ocular damage. End-stage renal failure is reached by 10 years of age. Accumulation of cystine in all tissues eventually leads to multisystemic disease. Treatment with cysteamine, which reduces the concentration of intracellular cystine, delays disease progression but has undesirable side effects. We report the first Ctns knockout mouse model generated using a promoter trap approach. We replaced the last four Ctns exons by an internal ribosome entry site-␤gal-neo cassette and showed that the truncated protein was mislocalized and nonfunctional. Ctns ؊/؊ mice accumulated cystine in all organs tested, and cystine crystals, pathognomonic of cystinosis, were observed. Ctns ؊/؊ mice developed ocular changes similar to those observed in affected individuals, bone defects and behavioral anomalies. Interestingly, Ctns ؊/؊ mice did not develop signs of a proximal tubulopathy, or renal failure. A preliminary therapeutic trial using an oral administration of cysteamine was carried out and demonstrated the efficiency of this treatment for cystine clearance in Ctns ؊/؊ mice. This animal model will prove an invaluable and unique tool for testing emerging therapeutics for cystinosis.

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“…4,7 -15 Some phenotypic correlation has been reported, and disease severity appears correlated to the expression of the gene product cystinosin. 8,15,21,22 Infantile cystinosis is because of a homozygous or compound heterozygous state of deletions or mutations causing truncated protein or involving the TM domains. The 57-kb deletion accounts for about 50% of cystinotic chromosomes in European populations, while a study in French -Canadian patients showed a much lower frequency, reflecting an Irish origin.…”

Section: Discussionmentioning

confidence: 99%

Mutational spectrum of the CTNS gene in Italy

et al. 2003

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Classic nephropathic or infantile cystinosis (NC) is an autosomal recessive disorder; the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we report the CTNS mutations identified in 42 of 46 Italian families with NC. The percentage of mutations characterized in this study is 86%. The mutational spectrum of the Italian population is different from that of populations of North European origin: the 57-kb deletion is present in a lower percentage, while the splicing mutations represent 30% of mutation detected in our sample. In all, six novel mutations have been identified, and the origin of one recurrent mutation has been traced.

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Mutations of CTNS Causing Intermediate Cystinosis

Cited by 72 publications

References 12 publications

Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis

Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis

Intralysosomal Cystine Accumulation in Mice Lacking Cystinosin, the Protein Defective in Cystinosis

Mutational spectrum of the CTNS gene in Italy

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