Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the &lt;b&gt;&lt;i&gt;CTNS&lt;/i&gt;&lt;/b&gt; Gene, and Potential for Repair

David, Dries; Berlingerio, Sante Princiero; Elmonem, Mohamed A.; Arcolino, Fanny Oliveira; Soliman, Neveen A.; Heuvel, Bert van den; Gijsbers, Rik; Levtchenko, Elena

doi:10.1159/000495270

Cited by 51 publications

(48 citation statements)

References 53 publications

(74 reference statements)

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“…In general, the detection rate of CTNS mutations in patients with clinical diagnosis of cystinosis is~95% by Sanger sequencing [15,23]. However, Shotelersuk et al failed to identify mutations in the CTNS gene in 19% of American cystinosis patients because the CTNS promoter was not analyzed [24].…”

Section: Discussionmentioning

confidence: 99%

“…The most common mutation in the Northern European population is a large 57-kb deletion, affecting the first 10 exons of CTNS [12][13][14]. Over 140 different pathogenic CTNS mutations have been identified in diverse world populations, including 57 missense and nonsense mutations, 23 intronic mutations, 45 deletions, 13 small insertions, 4 indels and 3 promoter region mutations [15].…”

Section: Introductionmentioning

confidence: 99%

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CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report

et al. 2019

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Background: Cystinosis is an autosomal recessive lysosomal storage disorder characterized by accumulation of cystine in lysosomes throughout the body. Cystinosis is caused by mutations in the CTNS gene that encodes the lysosomal cystine carrier protein cystinosin. CTNS mutations result in either complete absence or reduced cystine transporting function of the protein. The diagnosis of nephropathic cystinosis is generally based on measuring leukocyte cystine level, demonstration of corneal cystine crystals by the slit lamp examination and confirmed by genetic analysis of the CTNS gene. Case presentation: A boy born to consanguineous Caucasian parents had the characteristic clinical features of the infantile nephropathic cystinosis including renal Fanconi syndrome (polydipsia/polyuria, metabolic acidosis, hypokalemia, hypophosphatemia, low molecular weight proteinuria, glycosuria, cystine crystals in the cornea) and elevated WBC cystine levels. Initially we performed RFLP analysis of the common in the Northern European population 57-kb deletion of proband's DNA, then a direct Sanger sequencing which revealed no mutations in the coding part of the CTNS gene. To confirm the diagnosis we performed RT-PCR analysis of total RNA obtained from patient-derived fibroblasts in combination with cDNA sequencing. This revealed the skipping of exon 4 and exon 5 in the CTNS in our patient. Therefore, we detected a novel 9-kb homozygous deletion in the CTNS gene at genomic DNA level, spanning region from intron 3 to intron 5. In order to identify the inheritance pattern of the deletion we analyzed DNA of proband's mother and father. Both parents were found to be heterozygous carriers of the CTNS mutation. Conclusions: Analysis of CTNS gene transcript allowed to identify a large homozygous deletion in the patient with infantile nephropathic cystinosis. Mutational detection at RNA level may be an efficient tool to establish the genetic defect in some cystinosis patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report

et al. 2019

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“…Defects in cystinosin may lead to cystine accumulation and the formation of intralysosomal crystals. The tissues impacted, severity and age of onset are dependent upon the patient's CTNS genotype [16]. Mutations that result in a loss of cystine transport are associated with severe infantile presentation of the disease.…”

Section: Cystinosismentioning

confidence: 99%

“…Mutations that result in a loss of cystine transport are associated with severe infantile presentation of the disease. Identification of mutations that inhibit transport activity can also be observed in individuals with later, juvenile onset disease suggesting that there may be additional cystinosin functions outside of cystine transport which contribute to some aspects of the disease [16]. Cystine accumulation within lysosomes can be reduced through cysteaminemediated conversion of cystine to cysteine, which can then be removed from the lysosome [17].…”

Section: Cystinosismentioning

confidence: 99%

ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease

Kerem

2020

Expert Opinion on Investigational Drugs

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Introduction: ELX-02, an investigational compound that is structurally an aminoglycoside analog, induces read-through of nonsense mutations through interaction with the ribosome, through which full-length functional proteins can be produced. It is being developed as a therapy for genetic diseases caused by nonsense mutations such as cystic fibrosis (CF) and nephropathic cystinosis. In Phase 1 clinical trials, 105 volunteers were exposed to ELX-02. To date, ELX-02 is well tolerated and there has been no reported treatment-related serious adverse events or deaths. Areas Covered: The development of this molecule, from its pharmacology to the ongoing Phase 2 clinical trials is discussed. Expert Opinion: Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases. In CF and nephropathic cystinosis, they comprise from 10% to 12% of the disease-causative alleles. ELX-02 is in development as a therapeutic for patients with these alleles as in vitro and in vivo data demonstrated dose-dependent read-through of nonsense mutations to produce full-length, functional proteins. Since read-through efficiency varies between alleles and mRNA context, careful consideration of target patient populations is required. The results to date support the ongoing Phase 2 clinical evaluations of ELX-02 as a read-through agent.

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“…Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease caused by biallelic mutations in the CTNS gene, which encodes a protein (cystinosin) that transports cystine out of lysosomes (Gahl et al 1982; Town et al 1998; Kalatzis & Antignac 2003; David et al 2019). Lysosomal storage of cystine damages several organs and different ophthalmic structures, including the cornea (Gahl et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Establishing an objective biomarker for corneal cystinosis using a threshold‐based Spectral domain optical coherence tomography imaging algorithm

Keidel

Elhardt

Hohenfellner

et al. 2020

Acta Ophthalmologica

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Purpose The purpose of the present study was to establish a semi‐automated threshold‐based image segmentation algorithm to detect and objectively quantify corneal cystine crystal deposition in ocular cystinosis with anterior segment optical coherence tomography (AS‐OCT). Methods This prospective, observational, comparative study included 88 eyes of 45 patients from the German Cystinosis Registry Study as well as 68 eyes of 35 healthy control subjects. All eyes were imaged with AS‐OCT (Cirrus HD‐OCT 5000, Carl Zeiss Meditec AG, Jena, Germany). As an initial step, B‐scan images were subjectively analysed for typical changes in morphology in comparison to healthy controls. Based on the experience gained, an objective semi‐automated B‐scan image segmentation algorithm was developed using a grey scale value‐based threshold method to automatically quantify corneal crystals. Results On AS‐OCT B‐scans, corneal crystals appeared as hyperreflective deposits within the corneal stroma. The crystals were distributed either in all stromal layers (43 eyes, 49%) or confined to the anterior (23 eyes, 26%) or posterior stroma (22 eyes, 25%), respectively. The novel automatic B‐scan image segmentation algorithm was most efficient in delineating corneal crystals at higher grey scale thresholds (e.g. 226 of a maximum of 255). Significant differences in suprathreshold grey scale pixels were observable between cystinosis patients and healthy controls (p < 0.001). In addition, the algorithm was able to detect an age‐dependent depth distribution profile of crystal deposition. Conclusion Objective quantification of corneal cystine crystal deposition is feasible with AS‐OCT and can serve as a novel biomarker for ocular disease control and topical treatment monitoring.

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Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the <b><i>CTNS</i></b> Gene, and Potential for Repair

Cited by 51 publications

References 53 publications

CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report

CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report

ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease

Establishing an objective biomarker for corneal cystinosis using a threshold‐based Spectral domain optical coherence tomography imaging algorithm

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