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  • 1
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    Kidney International 67 (2), 443-448 
    Keywords: EXPRESSION ; screening ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; PATIENT ; kidney ; MESSENGER-RNA ; TRANSCRIPTION FACTOR ; IDENTIFICATION ; MUTATIONS ; development ; methods ; MOLECULAR-GENETICS ; XENOPUS-LAEVIS OOCYTES ; AMINO-ACID-TRANSPORT ; CANADA ; cystinuria ; QUEBEC ; RBAT ; SLC3A1 ; SLC7A9
    Abstract: Background. Cystinuria is an inherited disorder of luminal reabsorptive transport for cystine and dibasic amino acids in the renal proximal tubule. Two cystinuria genes have been identified. Mutations of SLC7A9, which encodes the luminal transport channel itself, tend to be dominant and mutations of SLC3A1 (rBAT), which encodes a transporter subunit, are always recessive. Patients who inherit two recessive mutations or two dominant mutations have equally severe forms of cystinuria. Heterozygotes excrete cystine in the normal (type I), moderate (type III), or high stone-forming (type II) range. Methods. Infants with cystinuria were identified via the Quebec Newborn Urinary Screening Program. In a subgroup of these infants, cystinuria was severe in the first months of life, but partially resolved by 2 to 4 years postnatally. We assigned each patient a final cystinuria phenotype at 3 to 4 years. In addition, we characterized SLC3A1 gene expression in fetal and postnatal human kidney. Results. Most infants with transient neonatal cystinuria are eventually classified as type III heterozygotes. All infants with mutant cystinuria genes have exaggerated neonatal cystine excretion except those who inherit two SLC3A1 mutations (type I/I cystinuria); these children have persistent severe cystinuria, implying that wildtype SLC3A1 is required for the maturational effect. Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney. Conclusion. Maturation of SLC3A1 gene expression between midgestation and 4.5 years postnatal age may account for transient neonatal cystinuria
    Type of Publication: Journal article published
    PubMed ID: 15673291
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  • 2
    Keywords: GENE ; GENES ; PATIENT ; COMPLEX ; COMPLEXES ; kidney ; RAT-KIDNEY ; SEQUENCES ; TRANSPORT ; MUTATION ; genetics ; MUTATIONS ; methods ; AMINO-ACID-TRANSPORT ; CANADA ; cystinuria ; SLC3A1 ; SLC7A9 ; amino acid ; EXPRESSION CLONING ; inherited disorder ; KIDNEY CDNA ; microcrystals ; stone
    Abstract: Background. Cystinuria is an inherited disorder of cystine and dibasic amino acid transport in kidney. Subtypes are defined by the urinary cystine excretion patterns of the obligate heterozygous parents: Type I/N (fully recessive or silent); Type II/N (high excretor); Type III/N (moderate excretor). The first gene implicated in cystinuria (SLC3A1 ) is associated with the Type I urinary phenotype. A second cystinuria gene (SLC7A9 ) was recently isolated, and mutations of this gene were associated with dominant (non-Type I) cystinuria alleles. Here we report genotype-phenotype studies of SLC7A9 mutations in a cohort of well-characterized cystinuria probands and their family members. Methods. Individual exons of the SLC7A9 gene were screened by single strand conformation polymorphism (SSCP) analysis and sequencing of abnormally migrating fragments. Results. Seven mutations were identified. A single bp insertion (799insA) was present in four patients: on Type III alleles in two patients and on Type II alleles in two patients. These results suggest that Type II and Type III may be caused by the same mutation and, therefore, other factors must influence urinary cystine excretion. A 4bp deletion in intron 12 (IVS12+4delAGTA) and a missense mutation (1245G--〉A, A354T) were identified on Type III alleles. A nonsense codon (1491G--〉T, E436X) and a possible splicing mutation (IVS9-17G--〉A) were seen in a Type I/III patient, but the mutations could not be assigned to particular alleles. Of additional interest were two missense mutations (316T--〉C, I44T and 967C--〉T, P261L) linked to Type I alleles. Conclusion. Our results provide evidence that some SLC7A9 mutations may be associated with fully recessive (Type I) forms of cystinuria. We also demonstrate SLC7A9 mutations in dominant Types II and III cystinuria. The finding of SLC7A9 mutations in all three subtypes underscores the complex interactions between specific cystinuria genes and other factors influencing cystine excretion. A simpler phenotypic classification scheme (recessive and dominant) for cystinuria is warranted
    Type of Publication: Journal article published
    PubMed ID: 12371955
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  • 3
    Keywords: EXPRESSION ; GENE ; REQUIRES ; TRANSFORMATION ; WNT ; kidney development ; METANEPHRIC MESENCHYME
    Abstract: beta-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target beta-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional beta-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplastic with a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional beta-catenin knockout mice revealed that these "parietal podocytes" derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that beta-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells.
    Type of Publication: Journal article published
    PubMed ID: 22021707
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  • 4
    ISSN: 0888-7543
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1998
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fifty-one patients aged 1 year to 56 years with metabolic bone disease underwent renal ultrasound. Medullary nephrocalcinosis was found in nine of 24 patients with X-linked hypophosphatemic rickets and is considered to be iatrogenic, related to vitamin D therapy. Another three in this group of 24 with both medullary and cortical increased renal echogenicity had suffered from repeated episodes of vitamin D intoxication and had secondary hyperparathyroidism. Nephrocalcinosis was less frequent in patients with treated vitamin D-dependent rickets or hypophosphatemic bone disease where generally smaller doses of vitamin D are given. Patients with pseudohypoparathyroidism, on small doses of vitamin D, had a normal renal ultrasound. In cystinosis and Fanconi's syndrome, the kidneys are small, echodense (both the cortex and medulla) with a tendency to cyst formation.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-198X
    Keywords: Key words Cystinosis ; Transplantation ; Proteinuria ; Polyuria ; Graft thrombosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Because cystinotic patients are polyuric and may have severe proteinuria, each of which is a potential risk factor for graft thrombosis, preemptive transplantation for them is questionable. The objectives of this study were to characterize the changes in urine volume and protein excretion at various stages of cystinosis, determine whether there is serologic evidence of hypercoagulability, and review the clinical experience in renal transplantation in cystinotic children. The records of cystinotic patients followed at the Montréal Children’s Hospital between 1992 and 1998 were reviewed. Urinary volume, protein excretion, and coagulation markers were collected to determine glomerular filtration rate (GFR) 〉50 ml/min/1.73 m2, 〈20 ml/min/1.73 m2, before and after starting dialysis. In addition, graft failure and graft thrombosis rates were obtained from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database. Urinary volume and protein excretion remained elevated throughout different phases of the disease. Coagulation factors were within normal limits for all patients. In the NAPRTCS database there were four thromboses among the 114 patients transplanted cystinotic patients. All these occurred in cadaveric grafts and only one occurred after preemptive transplantation. Despite polyuria and severe proteinuria, children with cystinosis do not appear to be at an increased risk of graft failure or graft thrombosis.
    Type of Medium: Electronic Resource
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