Phenotypic and genetic heterogeneity in Dent's disease—the results of an Italian collaborative study

Tosetto, Enrica; Ghiggeri, Gian Marco; Emma, Francesco; Barbano, G; Carrea, Alba; Vezzoli, Giuseppe; Torregrossa, Rossella; Cara, M; Ripanti, Gabriele; Ammenti, Anita; Peruzzi, Licia; Murer, Luisa; Ratsch, Ilse Maria; Citron, L.; Gambaro, Giovanni; D’Angelo, Angela; Anglani, Franca

doi:10.1093/ndt/gfl274

Cited by 50 publications

(68 citation statements)

References 44 publications

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“…Consequently, the t → c transition resulted in skipping of exon 3, and a smaller mRNA transcript. This aberrant processing of pre-mRNA is consistent with that reported in a patient carrying a mutation affecting the g nucleotide at position +1 bp of the donor splice site consensus sequence [27], and in another patient carrying a mutation affecting the a nucleotide at position –2 bp of the acceptor splice site consensus sequence of intron 2 [28]. The mutant pre-mRNA transcript would either lead to mRNA degradation through nonsense-mediated decay [24] or, if translated, to a frameshift with a missense peptide from codon 36 and a premature termination at codon 38.…”

Section: Resultssupporting

confidence: 90%

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Reed²,

Williams³

et al. 2009

Nephron Physiol

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Background/Aims: Dent’s disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. Methods: Eighteen probands with Dent’s disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. Results: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. Conclusions: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease in this patient cohort.

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Section: Resultssupporting

confidence: 90%

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Reed²,

Williams³

et al. 2009

Nephron Physiol

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“…Excepting very few cases, the OCRL mutations associated with Dent disease 2 do not overlap with those causing Lowe syndrome. 10,20,24 Missense mutations occur in the middle region of the gene (exons 9-15), whereas truncating mutations are found exclusively in the first 7 exons; the OCRL mutations associated with Lowe syndrome are located instead in the 3 0 region of the gene (exons [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and involve all three functional OCRL1 domains, whereas frameshift and nonsense mutations cluster in exons [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The different distribution of OCRL mutations in Dent disease 2 and Lowe syndrome suggests a genotype-phenotype correlation that has yet to be thoroughly explored.…”

Section: Resultsmentioning

confidence: 99%

“…Primers and PCR conditions for amplifying the coding region, intron-exon boundaries, and 5 0 UTR exons of the CLCN5 gene have been described elsewhere. 21 The PCR products were analyzed using the Agilent bioanalyzer (Agilent Technologies, Waldbronn, Germany) and purified with the QIAquick DNA purification kit (Qiagen GmbH, Hilden, Germany). Direct automated PCR product sequencing was done with the ABI PRISM GENESCAN 373A DNA sequencer and the BigDye Terminator v1.1 Cycle Sequencing Kit (PE Applied Biosystems, Foster City, CA, USA).…”

Section: Case Reportmentioning

confidence: 99%

“…Total RNA was extracted from the patient's and his mother's leukocytes using Trizol reagent (Life Technologies, Monza, Italy) according to the manufacturer's instructions, and 0.2 mg of total RNA was reverse transcribed using the TaqMan multiscribe RT-PCR system (PE Applied Biosystems). Five microlitre of cDNA were amplified using a forward primer located in exon 4 (5 0 -GTTCAAGAAGCAGAAGAAACTCT-3 0 ) and a reverse primer located in exon 7 (5 0 -GTCTTCAAATCCAAGAAGCC-3 0 ), and PCR conditions according to Addis et al 21 PCR products were purified and directly sequenced on ABI 3130XL apparatus (PE Applied Biosystems).…”

Section: Case Reportmentioning

confidence: 99%

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An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

et al. 2012

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Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388 þ 3A4G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.

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“…9 However, Copelovitch et al suggested that the diagnosis should be considered in patients with nephrotic proteinuria without hypoalbuminemia or edema and FSGS. 10 This is important to avoid immunosuppressors as in Case 1.…”

Section: Discussionmentioning

confidence: 99%

Uso a longo prazo de enalapril e hidroclorotiazida em dois pacientes com novas mutações com doença de Dent tipo 1

et al. 2012

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Dent's disease type 1 is an X-linked tubular disease caused by mutations in the renal chloride channel CLCN-5, and it is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal failure. Several cases have been described in which the only presenting symptoms were asymptomatic proteinuria, and focal segmental or global glomerulosclerosis. The renal failure in these patients may be caused by hypercalciuria and persistent proteinuria. Therefore, angiotensin converse enzyme inhibitor and thiazides could be useful. Our aim is to report the effects of these drugs in two novel mutations patients with Dent's disease type 1. In this report, no significant correlations between dosage of hydrochlorothiazide and calciuria and no significant correlations between proteinuria and dosage of enalapril were detected. This is important since these are polyuric patients and these drugs could be dangerous to their renal function. Keywords:Enalapril. Proteinuria. Hypercalciuria.Hydrochlorothiazide. Dent Disease. resumoA doença de Dent é uma tubulopatia ligada ao X causada por mutações no gene que codifica o canal de cloro CLCN-5 e é caracterizada por proteinúria de baixo peso molecular, hipercalciúria, nefrocalcinose e insuficiência renal. Vários casos têm sido descritos, nos quais o único sintoma na apresentação foi proteinúria assintomática e glomerulosclerose global ou segmentar. A insuficiência renal nesses pacientes pode ser causada pela hipercalciúria e proteinúria persistente. Portanto, o inibidor da enzima de conversão da angiotensina e os tiazídicos poderiam ser úteis. O objetivo desta pesquisa é relatar os efeitos destas drogas em dois pacientes com doença de Dent tipo 1 com mutações novas. Neste relato não foram observadas correlações significativas entre dose de hidroclorotiazida e calciúria e entre enalapril e proteinúria. Este achado é importante, pois, sendo pacientes poliúricos, o uso destas drogas poderia prejudicar a função renal Palavras-chave: Enalapril. Proteinúria. Hipercalciúria. Hidroclorotiazida. Doença de Dent.

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Phenotypic and genetic heterogeneity in Dent's disease—the results of an Italian collaborative study

Abstract: Our data confirm the genetic heterogeneity of Dent's disease. In most classic cases, the clinical diagnosis is confirmed by genetic tests.

Cited by 50 publications

References 44 publications

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

Uso a longo prazo de enalapril e hidroclorotiazida em dois pacientes com novas mutações com doença de Dent tipo 1

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