Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai‐Barrow syndrome

Anglani, Franca; Terrin, Liliana; Brugnara, Milena; Battista, Michèle; Cantaluppi, Vincenzo; Ceol, Monica; Bertoldi, Loris; Valle, Giorgio; Joy, Maliackal Poulo; Pober, Barbara R.; Longoni, Mauro

doi:10.1111/cge.13242

Cited by 16 publications

(23 citation statements)

References 4 publications

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“…3,4 Individuals homozygous for LRP2 R3192Q do not present with obvious craniofacial malformations, recapitulating earlier observations that missense mutations in LRP2 feature mild forms or even the absence of forebrain anomalies. 8,9 However, both individuals present with severe myopia (þ7 and þ9 dioptres, respectively), indicating massive overgrowth of the eyes as a consequence of potentially impaired uptake of SHH-N 3 and other megalin ligands 5 in the retinal pigment epithelium. Although aberrant targeting of megalin R3192Q to lysosomes has only been shown directly in NPCs, the ability of SHH-N to induce the decay of the mutant receptor in iPSC-derived RPTECs strongly argues that a similar disease mechanism is operable in the kidney and responsible for renal Fanconi syndrome in this family with DBS.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 Some variability exists in the extent of malformation of forebrain and facial structures in patients with DBS, defects attributed to the loss of receptor expression in neuroepithelial cells of the developing central nervous system. 2,[8][9][10] By contrast, patients with DBS invariably suffer from renal resorption defects (renal Fanconi syndrome) characterized by urinary loss of megalin ligands, including vitamins D, A, and B12 bound to their plasma carrier proteins. 1,11,12 This observation underscores the central role played by megalin in proximal tubular retrieval processes in humans.…”

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confidence: 99%

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Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Flemming¹,

Marczenke²,

Rudolph³

et al. 2020

Kidney International

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Donnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2, encoding the multifunctional endocytic receptor megalin. Here, we identified a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Using patient-derived induced pluripotent stem cell lines we generated neuroepithelial and kidney cell types as models of the disease. Using these cell models, we documented the inability of megalin R3192Q to properly discharge ligand and ligand-induced receptor decay in lysosomes. Thus, mutant receptors are aberrantly targeted to lysosomes for catabolism, essentially depleting megalin in the presence of ligand in this affected family.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Flemming¹,

Marczenke²,

Rudolph³

et al. 2020

Kidney International

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“…WES results seem to support this hypothesis. In addition to BDA, who has already been described as carrying biallelic mutations in the LRP2 gene [64], AMV was also found to carry a known pathogenic LRP2 allele and a very rare inframe deletion in the CUBN gene. CUBN variants have recently been associated with proteinuria with no signs of IGS.…”

Section: Discussionmentioning

confidence: 97%

“…However, apart from BDA who was found to carry biallelic pathogenic variants in the LRP2 gene and, for this reason, and after a careful clinical revaluation, was assessed to suffer from an atypical form of DB/FOAR syndrome [64], the other patient (AMS) did not suffer from cystinuria, despite carrying biallelic variants in the SLC3A1 gene that were classified as likely pathogenic according to ACMG/AMP variant interpretation. Indeed, in this patient, the urinary level of cysteine was found to be normal even after repeated measurements.…”

Section: Discussionmentioning

confidence: 99%

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Gianesello

Ceol

Bertoldi

et al. 2020

IJMS

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Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

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“…they are genetically unsolved (Lieske et al 1993). As mentioned earlier, when NGS-either of target genes or using genetic panels-was used to investigate such cases, no other disease-causing genes were identified (Zhang et al 2017b;Anglani et al 2018;Gianesello et al 2020a).…”

Section: Diagnosing Dent Diseasementioning

confidence: 99%

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

et al. 2020

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Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are known to cause Dent disease, no such mutations are found in about 25-35% of cases, making diagnosis more challenging. This review outlines current knowledge regarding Dent disease from another perspective. Starting from the history of Dent disease, and reviewing the clinical details of patients with and without a genetic characterization, we discuss the phenotypic and genetic heterogeneity that typifies this disease. We focus particularly on all those confounding clinical signs and symptoms that can lead to a misdiagnosis. We also try to shed light on a concealed aspect of Dent disease. Although it is a proximal tubulopathy, its misdiagnosis may lead to patients undergoing kidney biopsy. In fact, some individuals with Dent disease have high-grade proteinuria, with or without hematuria, as in the clinical setting of glomerulopathy, or chronic kidney disease of uncertain origin. Although glomerular damage is frequently documented in Dent disease patients' biopsies, there is currently no reliable evidence of renal biopsy being of either diagnostic or prognostic value. We review published histopathology reports of tubular and glomerular damage in these patients, and discuss current knowledge regarding the role of CLCN5 and OCRL genes in glomerular function.

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Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai‐Barrow syndrome

Cited by 16 publications

References 4 publications

Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

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