The Clinical and Mutational Spectrum of Turkish Patients with Cystinosis

Topaloğlu, Rezan; Gülhan, Bora; İnözü, Mihriban; Canpolat, Nur; Yılmaz, Alev; Noyan, Aytül; Dursun, İsmail; Gökçe, İbrahim; Gürgöze, Metin Kaya; Akıncı, Nurver; Baskın, Esra; Serdaroğlu, Erkin; Kılıç, Beltinge Demircioğlu; Yüksel, Selçuk; Hacıhamdioğlu, Duygu Övünç; Korkmaz, Emine; Hayran, Mutlu; Özaltın, Fatih

doi:10.2215/cjn.00180117

Cited by 22 publications

(30 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we distinguished three functional groups: those that led to the synthesis of a cystinosin variant with residual cystin efflux activity (RA, residual activity), those that led to the synthesis of an inactive cystinosin variant (IP, inactive protein), and those that did not allow for the protein to be translated and present at the lysosome membrane (AP, absent protein). The justification of mutations classification is proposed in Table 5 [ 2 , 20 , 21 , 22 , 23 , 24 ]. The localization of the different mutations is illustrated in Figure 2 [ 1 , 2 , 20 , 23 , 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…The genotype/phenotype analysis that we propose hinges on the first rational classification of mutations in the CTNS gene and is based on the functional consequences of these mutations on the structure of cystinosin. The justification of mutations classification is based on a multi-disciplinary approach taking into account both published experimental data and patients’ clinical phenotype, with a discussion involving physicians, biochemists, geneticists, and basic scientists [ 2 , 20 , 21 , 22 , 23 ]. In light of the results, this classification appears relevant since it makes it possible to predict a response profile to cysteamine as a function of the patient’s underlying genotype.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation

Quinaux

Bertholet‐Thomas

Boyer

et al. 2021

Cells

View full text Add to dashboard Cite

Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2–61) years, and a eGFR of 64 (23–149) mL/min/1.73m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation

Quinaux

Bertholet‐Thomas

Boyer

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…1 Percentage of the patients with gastrointestinal complications according to leucocyte cystine level registry and confirmed that none of the patients had thee 57-kb CTNS deletion. In that study, the most common alleles in Turkey is c.681G.A (p.E227E; 31%), c.1015G.A (p.Gly339Arg; 22%) and c.18_21 del (p.Thr7Phefs*7; 14%) [29]. Consistent with this result, in our study, the most common mutation was c.1015G > A [p.Gly339Arg] (20%) followed by c.681G > A [p.Glu227-Glu] (16.7%).…”

Section: Discussionmentioning

confidence: 89%

Cystinosis beyond kidneys: gastrointestinal system and muscle involvement

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Cystinosis is a multisystemic disease resulting from cystine accumulation primarily in kidney and many other tissues. We intended to study the evolution of less commonly seen extrarenal complications of cystinosis in a group of patients who have periods without cysteamine treatment. Methods: Gastrointestinal and muscular complications of cystinosis were studied in a group of 21 patients. Results: Twenty one patients were included in the study. Among them, 14 were homozygous and 3 were compound heterozygous for CTNS mutations. The median age of diagnosis was 15 months (range; 5 months-14 years) and the mean age at last visit was 11.3 ± 6.5 years. Nine patients (42%) had end stage renal disease at a mean age of 10.6 years (6.5-17 years). Abdominal ultrasonography and portal vein doppler ultrasonography were performed in19 patients, 14 of them (74%) had hepatomegaly, 10 patients (53%) had granular pattern or heterogeneity of liver. Only one patient had high transaminase levels and liver biopsy showed cystine crystals in the liver. Eleven patients (58%) had borderline or increased portal vein minimum and maximum flow velocities. One patient had CK level of 9024 U/L and electromyographic study showed active myopathic involvement. Two patients were found to have gastroesaphageal reflux only and 4 patients were found to have esophageal remnants in addition to reflux. Conclusions: In addition to renal functions, extrarenal organs may be affected from cystine accumulation even in childhood, especially in patients who are incompliant to treatment, resulting in complications such as swallowing difficulty, hepatomegaly and portal hypertension.

show abstract

“…The breakpoints of this 57,257 base pair deletion locate in exon 10 of CTNS and intron 2/3 of TRPV1 , resulting in deletion of large parts of CTNS , all of CARKL/SHPK and the two non-coding exons of TRPV1 (13). However, in other populations, this deletion appears a lot less frequent and previous reports did not identify this allele in cystinosis cases from Middle Eastern countries including Egypt, Iran, Jordan, Turkey, and Saudi Arabia (14).…”

Section: Introductionmentioning

confidence: 79%

A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East

et al. 2019

View full text Add to dashboard Cite

Background: Nephropathic Cystinosis, the most common cause of renal Fanconi syndrome, is a lysosomal transport disorder with an autosomal recessive inheritance pattern. A large number of mutations in CTNS have been identified as causative to date. A 57 kb deletion encompassing parts of CTNS is most commonly identified in Caucasians but this allele has not been identified in individuals of Eastern Mediterranean, Middle Eastern, Persian, or Arab origin to date. Methods and Results: Implementing whole exome sequencing (WES) in a consanguineous Iranian family, we identified this large deletion affecting CTNS in a patient initially presenting with hypokalemic metabolic alkalosis symptoms and considerable proteinuria. Conclusion: We show WES is a cost and time efficient genetic diagnostics modality to identify the underlying molecular pathology in Cystinosis individuals and provide a summary of all previously reported CTNS alleles in the Middle east population. Our work also highlights the importance to consider the 57-kb deletion as underlying genetic cause in non-European populations, including the Middle East. Limited diagnostic modalities for Cystinosis in developing countries could account for the lack of previously reported cases in these populations carrying this allele. Further, our findings emphasize the utility of WES to define genetic causes in clinically poorly defined phenotypes and demonstrate the requirement of Copy number variation (CNV) analysis of WES data.

show abstract

The Clinical and Mutational Spectrum of Turkish Patients with Cystinosis

Abstract: The most common cystinosis gene mutations identified in Turkey were c.681G>A (p.Glu227Glu), c.1015G>A (p.Gly339Arg), and c.18_21 del (p.Thr7Phefs*7). Patients with less severe cystinosis gene mutations tend to have better kidney outcome.

Cited by 22 publications

References 20 publications

Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation

Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation

Cystinosis beyond kidneys: gastrointestinal system and muscle involvement

A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East

Contact Info

Product

Resources

About