Cystinosis as a lysosomal storage disease with multiple mutant alleles: Phenotypic-genotypic correlations (original) (raw)
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An Indian Boy with Nephropathic Cystinosis: A Case Report and Molecular Analysis of CTNS Mutation
Genetic Testing and Molecular Biomarkers, 2009
Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by excessive accumulation of cystine within the lysosome. Cystinosis is caused by mutations in the lysosomal cystine transporter, cystinosin (CTNS). The CTNS gene consists of 12 exons and encodes for an integral lysosomal membrane protein with seven transmembrane domains. A majority of cystinotic patients are European descents and only a few cases have been reported from other ethnic groups. Here we report a case of nephropathic cystinosis in an Indian boy born to consanguineous parents. Major symptoms of the patient include gross loss of weight, vomiting, dehydration and cystine crystals in the cornea. Ichthyosis on the arms and legs is also observed. Sequencing analysis of all the CTNS exons revealed that the proband is homozygous for a 3-bp in-frame deletion in exon 10, resulting in the loss of a conserved Ser270 within the fifth transmembrane domain of CTNS. His parents are both heterozygous for the same mutation.
Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis
Human Mutation, 2002
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.
Nephron
Mutations in the CTNS gene encoding the lysosomal membrane cystine transporter cystinosin are the cause of cystinosis, an autosomal recessive lysosomal storage disease. More than 140 CTNS mutations have been reported worldwide. Recent studies have discovered that cystinosin exerts other key cellular functions beyond cystine transport such as regulation of oxidative state, lysosomal dynamics and autophagy. Here, we review the different mutations described in the CTNS gene and the geographical distribution of incidence. In addition, the characteristics of the various mutations in relation to the functions of cystinosin needs to be further elucidated. In this review, we highlight the functional consequences of the different mutations in correlation with the clinical phenotypes. Moreover, we propose how this understanding would be fundamental for the development of new technologies through targeted gene therapy, holding promises for a possible cure of the kidney and extra-renal phenotypes of cystinosis.
Nephron
Mutations in the CTNS gene encoding the lysosomal membrane cystine transporter cystinosin are the cause of cystinosis, an autosomal recessive lysosomal storage disease. More than 140 CTNS mutations have been reported worldwide. Recent studies have discovered that cystinosin exerts other key cellular functions beyond cystine transport such as regulation of oxidative state, lysosomal dynamics and autophagy. Here, we review the different mutations described in the CTNS gene and the geographical distribution of incidence. In addition, the characteristics of the various mutations in relation to the functions of cystinosin needs to be further elucidated. In this review, we highlight the functional consequences of the different mutations in correlation with the clinical phenotypes. Moreover, we propose how this understanding would be fundamental for the development of new technologies through targeted gene therapy, holding promises for a possible cure of the kidney and extra-renal phenotypes of cystinosis.
BMC Nephrology
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 th...
Orphanet journal of rare diseases, 2016
Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the curre...
Late-Onset Nephropathic Cystinosis: Clinical Presentation, Outcome, and Genotyping
2008
Background and objectives: Cystinosis is an autosomal recessive disease characterized by the intralysosomal accumulation of cystine, as a result of a defect in cystine transport across the lysosomal membrane. Three clinical forms have been described on the basis of severity of symptoms and age of onset: infantile cystinosis, characterized by renal proximal tubulopathy and progression to end-stage renal disease before 12 yr of age; juvenile form, with a markedly slower rate of progression; and adult form, with only ocular abnormalities.
Infantile Nephropathic Cystinosis - Homozygous c.516dupC Mutation of the CTNS Gene
Medical Science and Discovery, 2022
Objective: Cystinosis is a rare, autosomal recessive, lysosomal storage disorder characterized by cystine accumulation throughout the body, due to mutations in the gene encoding cystinosin, named CTNS. Infantile nephropathic cystinosis (INC), the most severe form of the disease and the most common cause of renal Fanconi syndrome (FS), starts with proximal tubulopathy and causes renal failure and various extra-renal manifestations over the time. Case Presentation: The authors report a 15-month-old boy of Greek origin who presented with failure to thrive over the last 7 months and was noted to have decreased weight and short stature. The metabolic control showed normoglycemic glucosuria, significant proteinuria, and generalized aminoaciduria, suggesting FS. Sequencing analysis of the CTNS gene revealed the frameshift mutation c.516dupC in the homozygous state, confirming the diagnosis of INC. Only one compound heterozygous individual for this mutation has been reported before. Conclusion: The index case brings out a new correlation of the c.516dupC mutation in the homozygous state with a pure INC phenotype. Alongside, it reminds clinicians to consider cystinosis in the differential diagnosis of failure to thrive or short stature.