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

Addis, Maria; Meloni, Chantal; Tosetto, Enrica; Ceol, Monica; Cristofaro, Rosalba; Melis, Maria Paola; Vercelloni, Paolo Gilles; Prete, Dorella Del; Marra, Giuseppina; Anglani, Franca

doi:10.1038/ejhg.2012.225

Cited by 22 publications

(13 citation statements)

References 30 publications

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“…Dent disease is genetically heterogeneous: in published cohorts about 50%-60% of patients have Dent disease 1 caused by mutations of the CLCN5 gene and about 15% have Dent disease 2 caused by mutations in the OCRL gene. One case of coinheritance of mutations in both genes has been described in a patient with a phenotype close to Lowe syndrome [Addis et al, 2013]. In our cohort of 150 distinct families, Dent disease 1 represents 61% and Dent disease 2 represents 7% of the cases; most of these cases have been previously described [Hichri et al, 2011].…”

Section: Other Forms Of Dent Diseasementioning

confidence: 65%

Mutation Update of theCLCN5Gene Responsible for Dent Disease 1

et al. 2015

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Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

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Section: Other Forms Of Dent Diseasementioning

confidence: 65%

Mutation Update of theCLCN5Gene Responsible for Dent Disease 1

et al. 2015

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“…In a patient with tubular proteinuria, dysmorphic features, rickets, growth delay, mild cognitive and behavioral impairment, and peripapillary optic nerve atrophy with grey papillae, the co-inheritance of a CLCN5-and OCRL-mutation was found by Addis et al [136]. The OCRL splice defect observed (c.388+3A>G) locates in the region typically affected in Dent-2 disease cases and the authors suggested, that here the phenotype resulted from synergic interaction between the two mutations.…”

Section: Unusual Findings In Association With Lowe Syndromementioning

confidence: 88%

Lowe syndrome/Dent-2 disease: A comprehensive review of known and novel aspects

2015

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The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment and a renal proximal tubulopathy in almost all of the patients. Whereas the ocular manifestations and severe hypotonia are present at birth, the renal involvement appears within the first months of life. Patients show progressive growth retardation and may develop a debilitating arthropathy. Treatment is symptomatic and life span rarely exceeds 40 yr. The causative OCRL gene, encodes an inositol polyphosphate 5-phosphatase. OCRL mutations were not only found in classic Lowe syndrome, but also in milder affected patients, classified as having Dent-2 disease. There is a phenotypic continuum within patients with Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of enzyme function. Researchers have conducted a large amount of work to understand the etiology responsible for the disease. However, the mechanisms leading to the clinical manifestations are still poorly understood and we are far from an effective therapy. In this review, we have included well-established findings and the most recent progress in understanding Lowe syndrome and Dent-2 disease.

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“…An XLR example is Dent's disease (CLCN5 and OCRL). 78 Again, it is difficult to prove that one mutation/gene does not suffice to cause the disease. Another problem for AD inheritance is to evaluate whether all patients have both mutations in cis, and if so, why?…”

Section: Lesson 1: In the Digenic Inheritance Examples Found To Datementioning

confidence: 99%

Digenic inheritance in medical genetics

2013

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Digenic inheritance (DI) is the simplest form of inheritance for genetically complex diseases. By contrast with the thousands of reports that mutations in single genes cause human diseases, there are only dozens of human disease phenotypes with evidence for DI in some pedigrees. The advent of high-throughput sequencing (HTS) has made it simpler to identify monogenic disease causes and could similarly simplify proving DI because one can simultaneously find mutations in two genes in the same sample. However, through 2012, I could find only one example of human DI in which HTS was used; in that example, HTS found only the second of the two genes. To explore the gap between expectation and reality, I tried to collect all examples of human DI with a narrow definition and characterise them according to the types of evidence collected, and whether there has been replication. Two strong trends are that knowledge of candidate genes and knowledge of protein–protein interactions (PPIs) have been helpful in most published examples of human DI. By contrast, the positional method of genetic linkage analysis, has been mostly unsuccessful in identifying genes underlying human DI. Based on the empirical data, I suggest that combining HTS with growing networks of established PPIs may expedite future discoveries of human DI and strengthen the evidence for them.

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

Cited by 22 publications

References 30 publications

Mutation Update of theCLCN5Gene Responsible for Dent Disease 1

Mutation Update of theCLCN5Gene Responsible for Dent Disease 1

Lowe syndrome/Dent-2 disease: A comprehensive review of known and novel aspects

Digenic inheritance in medical genetics

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