Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0392525 (nephrolithiasis)
 2,669 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state.
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PMID:Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. 770 83

The oculocerebrorenal (Lowe) syndrome is an X-linked recessive disorder characterized by congenital cataracts, hypotonia, developmental delay, poor growth and renal tubular dysfunction. Although the disorder has been mapped to chromosome Xq24-26, the underlying metabolic defect remains unknown. The renal component of the Lowe syndrome comprises tubular dysfunction, that is tubular proteinuria and generalized aminoaciduria progressing to the renal Fanconi syndrome, with later glomerular disease. Clinical problems typically include polyuria, acidosis, hypophosphatemia with rickets and eventually end stage renal disease. Hypercalciuria and its sequelae (nephrocalcinosis and nephrolithiasis) have not been described as cardinal features of the untreated disorder although they reportedly complicate vitamin D and calcium therapy of rickets. We discuss 5 boys with congenital cataracts, hypotonia, developmental delay, failure to thrive and the renal Fanconi syndrome who were diagnosed with the Lowe syndrome and in whom hypercalciuria was documented at diagnosis. We conclude that hypercalciuria and its sequelae may occur commonly in patients with the Lowe syndrome as a component of tubular dysfunction or a complication of therapy.
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PMID:Hypercalciuria and nephrocalcinosis in the oculocerebrorenal syndrome. 786 19

X-linked recessive nephrolithiasis is associated with kidney stones and renal tubular dysfunction in childhood progressing to renal failure in adulthood. The primary defect causing this renal tubular disorder is unknown and determining the chromosomal location of the mutant gene would represent an important step toward defining the biochemical basis. We have performed linkage studies in 102 members (10 affected males, 47 unaffected males, 15 obligate heterozygote females, and 30 unaffected females) from five generations of one family. As genetic markers we used 10 cloned human X chromosome fragments identifying restriction fragment length polymorphisms and seven pairs of oligonucleotide primers identifying microsatellite polymorphisms. Linkage with the locus DXS255 was established with a peak LOD score = 5.91 at 3.6% recombination, thereby localizing the X-linked recessive nephrolithiasis gene to the pericentromeric region of the short arm of the X chromosome (Xp11.22). Multilocus analysis indicated that the mutant gene was distal to DXS255 but proximal to the Duchenne muscular dystrophy locus on Xp. Thus, the gene that causes X-linked recessive nephrolithiasis maps to the pericentromeric region of the short arm of the X chromosome (Xp11.22), and further characterization of this gene will help to elucidate the factors controlling renal tubular function and mineral homeostasis.
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PMID:Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies. 851 47

Kidney stones (nephrolithiasis), which affect 12% of males and 5% of females in the western world, are familial in 45% of patients and are most commonly associated with hypercalciuria. Three disorders of hypercalciuric nephrolithiasis (Dent's disease, X-linked recessive nephrolithiasis (XRN), and X-linked recessive hypophosphataemic rickets (XLRH)) have been mapped to Xp11.22 (refs 5-7). A microdeletion in one Dent's disease kindred allowed the identification of a candidate gene, CLCN5 (refs 8,9) which encodes a putative renal chloride channel. Here we report the investigation of 11 kindreds with these renal tubular disorders for CLCN5 abnormalities; this identified three nonsense, four missense and two donor splice site mutations, together with one intragenic deletion and one microdeletion encompassing the entire gene. Heterologous expression of wild-type CLCN5 in Xenopus oocytes yielded outwardly rectifying chloride currents, which were either abolished or markedly reduced by the mutations. The common aetiology for Dent's disease, XRN and XLRH indicates that CLCN5 may be involved in other renal tubular disorders associated with kidney stones.
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PMID:A common molecular basis for three inherited kidney stone diseases. 855 42

Mutations in the CLCN5 gene, mapped in Xp11.22, have been recently reported to be associated with X-linked nephrolithiasis, X-linked recessive hypophosphataemic rickets and Dent's disease. We report a missense mutation in exon 6 of the CLCN5 gene. The mutation in this pedigree is S244L, the same mutation as has previously been described in an Italian family showing a similar pathology. However, in the family reported here, affected males have developed neither nephrolithiasis nor nephrocalcinosis. The question arises whether we are dealing with a milder phenotype or whether a more severe pathology will develop with ageing.
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PMID:A second family with XLRH displays the mutation S244L in the CLCN5 gene. 918 73

This study demonstrates that a missense mutation in the voltage gated chloride channel, CLCN5, can cause X-linked renal failure without X-linked recessive hypophosphatemic rickets. A large kindred (Family A), initially evaluated in 1974 with an inherited syndrome characterized by hypercalciuria, nephrocalcinosis, low molecular weight proteinuria, renal tubular acidosis, and renal failure, was clinically re-evaluated and genetically characterized. Medical histories, physical examinations, blood chemistries, and 24-hour urine collections were obtained from 48 family members. Both female and male family members exhibited hypercalciuria, nephrolithiasis, and low molecular weight proteinuria. However, only men developed renal insufficiency, consistent with an X-linked recessive gene defect. Genetic linkage located the disease locus on the proximal short arm of the X chromosome (Xp11) where a voltage gated chloride channel gene, CLCN5, had previously been mapped. DNA sequence of the CLCN5 gene demonstrated a missense mutation (Ser244Leu) in affected family members. The same missense mutation has previously been shown to cause X-linked recessive hypophosphatemic rickets. No affected member of Family A had evidence of chronic hypophosphatemia, clinically significant rickets, or osteomalacia. We hypothesize that genetic background, environment, diet, or an unidentified modifying gene may account for the differing phenotypes resulting from this shared gene defect.
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PMID:CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets. 945 24

Mutations in the CLCN5 gene have been demonstrated in three disorders of hypercalciuric nephrolithiasis, i.e., Dent's disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets. Recently, a number of Japanese children with low molecular weight proteinuria (LMWP) showing symptoms similar to those shown by patients with Dent's disease in British families have also been reported to have mutations in the CLCN5 gene. The present study examines five unrelated Japanese families with LMWP, two of which lacked any signs other than LMWP, and three of which had several signs other than LMWP, i.e., hypercalciuria, aminoaciduria, hypophosphatemia, and rickets. One nonsense (E118X) and one missense (W22G) mutation were found in three patients in the two families having only LMWP. One genomic deletion including exons 5 to 8 in the CLCN5 gene was found in a patient with hypophosphatemic rickets, and a nonsense mutation (R347X) was found in one patient with LMWP and slight hypercalciuria. No mutations of the exons and exon-intron boundaries in the CLCN5 gene were found in one patient with LMWP, aminoaciduria, and hypokalemia. In addition to the predicted loss of chloride channel function in these nonsense and deletion mutations, the loss of function in the missense mutation W22G was confirmed in the Xenopus oocyte expression system. These results clarified four novel mutations in the CLCN5 genes, and additionally suggested that the loss-of-function mutation of the CLCN5 does not necessarily lead to hypercalciuria and nephrocalcinosis in the early stage of the disease, and that LMWP is an early and essential manifestation of disorders of the CLC-5 chloride channel.
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PMID:Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria. 959 78

We report a new X-linked recessive nephrolithiasis kindred. X-linked recessive nephrolithiasis is a recently described disease characterized by recurrent nephrolithiasis, nephrocalcinosis, and progressive renal failure, associated with mutations in a renal chloride channel gene, chloride channel number 5. Screening individuals at risk with renal ultrasonography and measurement of urinary excretion of low molecular weight proteins and calcium will exclude boys without X-linked recessive nephrolithiasis kindred and identify boys likely to have the disease.
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PMID:X-linked recessive nephrolithiasis: presentation and diagnosis in children. 960 82

X-linked recessive nephrolithiasis (XRN) is a rare hereditary form of progressive renal failure characterized by (1) proximal tubular dysfunction and low molecular weight proteinuria; (2) hypercalciuria with nephrocalcinosis and nephrolithiasis. Because the clinical features are non-specific and variable, affected families in different parts of the world were initially thought to have several distinct syndromes. However, positional cloning of the relevant gene (CLCN5) demonstrated that these families have, in common, mutations affecting a chloride channel expressed throughout the renal tubule. To expand the description of early clinical and pathological manifestations of XRN, we describe three patients diagnosed in the 1st decade of life. Renal tubular dysfunction may be evident even in the neonatal period, hypophosphatemic rickets may develop in the first years of life, and nephrocalcinosis (but not nephrolithiasis) with glomerulosclerosis are consistent features in childhood. One of our patients is indistinguishable from the others on clinical grounds, yet no mutations of the coding regions of the CLCN5 gene were found, raising the possibility of genetic heterogeneity in the XRN syndrome.
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PMID:Clinical features of X-linked nephrolithiasis in childhood. 981 83

This review describes the supposed mechanisms leading to idiopathic hypercalciuria (IHU) in childhood, further the diagnostic criteria and the proposed treatment modalities are discussed. IHU is not only one of the main causes of renal stone disease in children but it's also at the origin of the postglomerular haematuria and the frequency-dysuria syndrome. Its role in the development of osteoporosis in adults is also documented. The diagnosis of raised calcium excretion is based on age specific values during early infancy. In older children and adults a urinary calcium/creatinine ratio exceeding 0.6 mmol/mmol is regarded as elevated. Dietary calcium restriction can no longer be recommended for the treatment of IHU because it results in secondary hyperoxaluria and on the long-term causes decreased bone mineral density. Patients should be kept on dietary sodium restriction and high fluid intake. In cases IHU associated with recurrent episodes of macroscopic haematuria or recurrent stone disease a therapeutic trial with hydrochlorothiazide in the dose of 0.5-1 mg/kg/day with potassium-citrate supplementation and possibly magnesium citrate should be started. In some special forms of hypercalciuria such as the X-linked recessive nephrolithiasis syndrome or Bartter syndrome the localization and in some cases even the molecular mechanism of the events leading to increased calcium excretion are elucidated. In IHU enhanced Ca(++)-ATPase, and Na-Li countertransport activity and decreased Na+/K+ ATPase activity were described in the erythrocyte membrane model. It is expected that with the molecular genetic development the clinical classification of the hypercalciuric syndromes will become a rational genome-based one.
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PMID:[Idiopathic hypercalciuria in childhood]. 987


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