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Genes Oct 2021Dent disease is a rare X-linked renal tubulopathy due to and (DD2) mutations. mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is...
Dent disease is a rare X-linked renal tubulopathy due to and (DD2) mutations. mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of reported cases, it is still unclear whether it has a clinical picture distinct from LS. We retrospectively analyzed the phenotype and genotype of our cohort of 35 DD2 males and reviewed all published DD2 cases. We analyzed the distribution of mutations along the gene and evaluated the type and frequency of ES according to the type of mutation and localization in OCRL protein domains. The frequency of patients with at least one ES was 39%. Muscle findings are the most common ES (52%), while ocular findings are less common (11%). Analysis of the distribution of mutations revealed (1) truncating mutations map in the PH and linker domain, while missense mutations map in the 5-phosphatase domain, and only occasionally in the ASH-RhoGAP module; (2) five mutations cause both DD2 and LS phenotypes; (3) codon 318 is a DD2 mutational hot spot; (4) a correlation was found between the presence of ES and the position of the mutations along OCRL domains. DD2 is distinct from LS. The mutation site and the mutation type largely determine the DD2 phenotype.
Topics: Adolescent; Biological Variation, Population; Child; Child, Preschool; Female; Genetic Association Studies; Genetic Diseases, X-Linked; Genetic Pleiotropy; Genotype; Humans; Kidney; Male; Mutation, Missense; Nephrolithiasis; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 34680992
DOI: 10.3390/genes12101597 -
Journal of the American Dental... Sep 2018
Topics: Chronic Disease; Female; Humans; Inflammation; Oral Health; Pregnancy; Premature Birth
PubMed: 30165972
DOI: 10.1016/j.adaj.2018.07.009 -
Pediatric Nephrology (Berlin, Germany) Dec 2020Dent disease is associated with low molecular weight proteinuria and hypercalciuria and caused by pathogenic variants in either of two genes: CLCN5 (Dent disease 1) and... (Comparative Study)
Comparative Study
BACKGROUND
Dent disease is associated with low molecular weight proteinuria and hypercalciuria and caused by pathogenic variants in either of two genes: CLCN5 (Dent disease 1) and OCRL (Dent disease 2). It is generally not accompanied by extrarenal manifestations and it is difficult to distinguish Dent disease 1 from Dent disease 2 without gene testing. We retrospectively compared the characteristics of these two diseases using one of the largest cohorts to date.
METHODS
We performed gene testing for clinically suspected Dent disease, leading to the genetic diagnosis of 85 males: 72 with Dent disease 1 and 13 with Dent disease 2. A retrospective review of the clinical findings and laboratory data obtained from questionnaires submitted in association with the gene testing was conducted for these cases.
RESULTS
The following variables had significantly higher levels in Dent disease 2 than in Dent disease 1: height standard deviation score (height SDS), serum creatinine-based estimated GFR (Cr-eGFR) (median: 84 vs. 127 mL/min/1.73 m, p < 0.01), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum lactate dehydrogenase (LDH), serum creatine phosphokinase (CK), serum potassium, serum inorganic phosphorus, serum uric acid, urine protein/creatinine ratio (median: 3.5 vs. 1.6 mg/mg, p < 0.01), and urine calcium/creatinine ratio. There were no significant differences in serum sodium, serum calcium, alkaline phosphatase (ALP), urine β2-microglobulin, incidence of nephrocalcinosis, and prevalence of intellectual disability or autism spectrum disorder.
CONCLUSIONS
The clinical and laboratory features of Dent disease 1 and Dent disease 2 were shown in this study. Notably, patients with Dent disease 2 showed kidney dysfunction at a younger age, which should provide a clue for the differential diagnosis of these diseases.
Topics: Autism Spectrum Disorder; Body Height; Child; Child, Preschool; Chloride Channels; Genetic Diseases, X-Linked; Genetic Testing; Humans; Kidney Diseases; Male; Nephrolithiasis; Phosphoric Monoester Hydrolases; Retrospective Studies
PubMed: 32683654
DOI: 10.1007/s00467-020-04701-5 -
Pediatric and Developmental Pathology :... 2022The study aims to explore the clinicopathological features and whether the nonsense mutations of gene have effect on the renal expression of CLC-5 protein and...
The study aims to explore the clinicopathological features and whether the nonsense mutations of gene have effect on the renal expression of CLC-5 protein and megalin/cubilin complex in children with Dent-1 disease. The clinicopathological features and genetic examination of three patients with Dent-1 disease were investigated. The expression of CLC-5 and megalin/cubilin complex in renal tissues was detected by using immunohistochemistry method. Urinary albumin, α1-microglobulin, β2-microglobulin, retinol binding protein, and calcium levels were measured by immunonephelometry. Urinary calcium and low molecular weight proteinuria (LMWP) were enhanced in three patients, and two presented with nephrotic range proteinuria. Focal glomerular obsolescence, minor tubulointerstitial injury, and focal calcification in corticomedullary junction were found in one patient. Nonsense mutations of gene from their mothers were identified in all three patients with Dent-1 disease; however, the expression of CLC-5 protein was not decreased in renal tubular cells. As the receptor complex of albumin and LMWP reabsorption, the expression of megalin/cubilin in the brush border of proximal tubules was decreased in Dent-1 patients. Even if the renal CLC-5 protein is expressed normally, the reduced expression of megalin/cubilin in the brush border of renal proximal tubules may be helpful to understand the physiopathology of Dent-1 disease with nonsense mutations of gene.
Topics: Albumins; Calcium; Child; Chloride Channels; Codon, Nonsense; Dent Disease; Humans; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Proteinuria; Receptors, Cell Surface
PubMed: 35100899
DOI: 10.1177/10935266211065554 -
Swiss Dental Journal 2015TMJ-like symptoms as first sign of a tumorous disease. Metastasis as an uncommon origin of the symptoms (in German).
TMJ-like symptoms as first sign of a tumorous disease. Metastasis as an uncommon origin of the symptoms (in German).
PubMed: 26470719
DOI: 10.61872/sdj-2015-10-06 -
Clinical Calcium Feb 2016Serum level of phosphate is regulated by the kidney, especially proximal tubule. The transcellular transport of phosphate in the proximal tubule is mediated via Na... (Review)
Review
Serum level of phosphate is regulated by the kidney, especially proximal tubule. The transcellular transport of phosphate in the proximal tubule is mediated via Na dependent transporters, i.e., NPT2a and NPT2b at the luminal membrane, and unknown channel at the basolateral side. The transport of phosphate via NPT2a and NPT2b is further regulated by factors, such as PTH, FGF23, and 1,25(OH)(2)D. Several hereditary diseases that cause hypophoshatemia specically are known. In addition, dysfunction of proximal tubule may develop Fanconi syndrome, which also causes hypherphosphaturia. In this section, I describe the renal mechanisms of phosphate handling and the causes of hypophosphatemia along with its treatment.
Topics: Administration, Oral; Calcitriol; Chloride Channels; Dent Disease; Fanconi Syndrome; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Kidney Tubules, Proximal; Mitochondrial Diseases; Oculocerebrorenal Syndrome; Parathyroid Hormone; Phosphates; Phosphoric Monoester Hydrolases; Phosphorus Compounds; Sodium-Phosphate Cotransporter Proteins, Type IIa; Sodium-Phosphate Cotransporter Proteins, Type IIc; Vitamin D
PubMed: 26813509
DOI: No ID Found -
Biological Chemistry Dec 2015Mutations of the inositol-5-phosphatase OCRL cause Lowe syndrome and Dent-II disease. Both are rare genetic disorders characterized by renal defects. Lowe syndrome is... (Review)
Review
Mutations of the inositol-5-phosphatase OCRL cause Lowe syndrome and Dent-II disease. Both are rare genetic disorders characterized by renal defects. Lowe syndrome is furthermore characterized by defects of the eye (congenital cataracts) and nervous system (mental disabilities, hypotonia). OCRL has been localised to various endocytic compartments suggesting impairments in the endocytic pathway as possible disease mechanism. Recent evidence strongly supports this view and shows essential roles of OCRL at clathrin coated pits, transport of cargo from endosomes to the trans-Golgi network as well as recycling of receptors from endosomes to the plasma membrane. In particular in vitro and in vivo evidence demonstrates an important role of OCRL in recycling of megalin, a multi-ligand receptor crucial for reabsorption of nutrients in the proximal tubulus, a process severely impaired in Lowe syndrome patients. Thus defects in the endocytic pathway are likely to significantly contribute to the kidney phenotype in Lowe syndrome and Dent-II disease.
Topics: Coated Pits, Cell-Membrane; Endocytosis; Humans; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; Protein Binding; Signal Transduction
PubMed: 26351914
DOI: 10.1515/hsz-2015-0180 -
Current Opinion in Urology Sep 2018To summarize the latest findings of congenital and acquired diseases related to stone formation and help understanding the multitude of cofactors related to urolithiasis. (Review)
Review
PURPOSE OF REVIEW
To summarize the latest findings of congenital and acquired diseases related to stone formation and help understanding the multitude of cofactors related to urolithiasis.
RECENT FINDINGS
Urolithiasis is related to a broad spectrum of congenital and acquired diseases and its management varies according to the stone type, underlying disease or recurrence rate, but it also changes according to recent findings and developments. As prevalence of urolithiasis is constantly increasing, identification of high-risk stone formers and early treatment is essential. Therefore, genetic evaluation like whole exome sequencing becomes a pertinent part of further diagnostics.
SUMMARY
Stone formation is a very heterogeneous pathomechanism. This prompt us to look at every patient individually particularly in high-risk patients, including stone and 24-h-urine analysis and additional diagnostic work-up based on stone type or underlying disease.
Topics: Acidosis, Renal Tubular; Adenine Phosphoribosyltransferase; Cystic Fibrosis; Cystinuria; Dent Disease; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperoxaluria, Primary; Hyperparathyroidism; Immobilization; Inflammatory Bowel Diseases; Lesch-Nyhan Syndrome; Metabolic Syndrome; Metabolism, Inborn Errors; Nephrocalcinosis; Polycystic Kidney Diseases; Risk Factors; Sarcoidosis; Spinal Cord Injuries; Urinary Bladder, Neurogenic; Urinary Tract Infections; Urolithiasis; Xanthine Dehydrogenase
PubMed: 29957682
DOI: 10.1097/MOU.0000000000000522 -
Nephrology, Dialysis, Transplantation :... Jan 2022Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their...
BACKGROUND
Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1-7 lead to Dent disease-2, whereas those in exons 8-24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms.
METHODS
Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5' end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells.
RESULTS
We successfully cloned the novel isoform transcripts from OCRL exons 6-24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained <20% activity.
CONCLUSIONS
We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.
Topics: Dent Disease; HeLa Cells; Humans; Mutation; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases; Protein Isoforms
PubMed: 34586410
DOI: 10.1093/ndt/gfab274 -
Advances in Chronic Kidney Disease May 2022Recent advances in the management of kidney tubular diseases have resulted in a significant cohort of adolescents and young adults transitioning from pediatric- to... (Review)
Review
Recent advances in the management of kidney tubular diseases have resulted in a significant cohort of adolescents and young adults transitioning from pediatric- to adult-focused care. Most of the patients under adult-focused care have glomerular diseases, whereas rarer tubular diseases form a considerable proportion of pediatric patients. The purpose of this review is to highlight the clinical signs and symptoms of tubular disorders, as well as their diagnostic workup, including laboratory findings and imaging, during young adulthood. We will then discuss more common disorders such as cystinosis, cystinuria, distal kidney tubular acidosis, congenital nephrogenic diabetes insipidus, Dent disease, rickets, hypercalciuria, and syndromes such as Bartter, Fanconi, Gitelman, Liddle, and Lowe. This review is a practical guide on the diagnostic and therapeutic approach of tubular conditions affecting young adults who are transitioning to adult-focused care.
Topics: Acidosis, Renal Tubular; Adolescent; Adult; Child; Cystinosis; Diabetes Insipidus, Nephrogenic; Humans; Kidney Diseases; Young Adult
PubMed: 36084976
DOI: 10.1053/j.ackd.2021.11.004