Dent's Disease Research Articles

Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq)

BackgroundFemale Dent disease 1 patients with low-molecular-weight proteinuria (LMWP) due to CLCN5 gene mutation were rarely reported, and these cases that the people were also with Turner syndrome (TS) were even hardly documented before.Case presentationHere we report a 3-year and 11-month old Chinese girl with short stature who had a karyotype of 46,X,i(X)(q10) and a de novo pathogenic variant in the CLCN5 gene on the short arm of X chromosome. Laboratory examinations showed that the patient had LMWP, hypercalciuria, hypophosphatemia, delayed bone age, and genital dysplasia.ConclusionThe combination of i(X)(q10) and CLCN5 mutation causes the deletion of the wild-type CLCN5 allele that results in Dent-1 and TS. To the best of our knowledge, this is the first case that a female CLCN5 mutation hemizygote is diagnosed with Dent-1 and Turner syndrome due to isochromosome X. Also, our case has indicated that the prevalence of the situation may be largely underestimated because of the mild signs of females with Dent-1.

Etiological Profile of Nephrocalcinosis in Children from Southern India

To study the etiological profile and patterns of clinical presentation of nephrocalcinosis. In this observational study, patients 18 years or younger, referred to the pediatric nephrology clinic with nephrocalcinosis were evaluated for etiology. Symptoms/signs at presentation, estimated glomerular filtration rate (eGFR) at presentation and follow-up, and growth parameters were recorded. The etiology of nephrocalcinosis (n=54) included distal renal tubular acidosis (n=18; 33.3%), primary hyperoxaluria (n=9; 16.7%), Bartter syndrome (n=7; 13%), Dent disease (n=4; 7.4%), cystinosis, familial hypomagnesemia with hypercalciuria and idiopathic hypercalcemia of infancy (2 each). Idiopathic nephrocalcinosis was seen in 5 (9.3%) children. Clinical features included failure to thrive (53.7%), polyuria (44.4%), bony deformities (31.5%) and hypokalemic paralysis (11.1%). At a median (IQR) follow-up of 24 (8, 56) months, the mean (SD) eGFR had improved from 59 (25.5) to 77 (31.48) mL/min/1.73m2 (P<0.01). Consanguinity was present in 50% (27/54). Genetic analysis in 5 primary hyperoxaluria cases confirmed AGXT mutations in 4; and GRHPR mutation in 1 child. Distal RTA, primary hyperoxaluria and Bartter syndrome were the common etiologies of nephrocalcinosis in our patient population.

Dent disease: classification, heterogeneity and diagnosis.

Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction, which occurs almost exclusively in males. It mainly presents symptoms in early childhood and may progress to end-stage renal failure between the 3rd and 5th decades of human life. According to its various genetic basis and to clinical signs and symptoms, researchers define two forms of Dent disease (Dent diseases 1 and 2) and suggest that these forms are produced by mutations in the CLCN5 and OCRL genes, respectively. Dent diseases 1 and 2 account for 60% and 15% of all Dent disease cases, and their genetic cause is generally understood. However, the genetic cause of the remaining 25% of Dent disease cases remains unidentified. All relevant peer-reviewed original articles published thus far have been screened out from PubMed and have been referenced. Genetic testing has been used greatly to identify mutation types of CLCN5 and OCRL gene, and next-generation sequencing also has been used to identify an increasing number of unknown genotypes. Gene therapy may bring new hope to the treatment of Dent disease. The abuse of hormones and immunosuppressive agents for the treatment of Dent disease should be avoided to prevent unnecessary harm to children. The current research progress in classification, genetic heterogeneity, diagnosis, and treatment of Dent disease reviewed in this paper enables doctors and researchers to better understand Dent disease and provides a basis for improved prevention and treatment.

Loss of CLC‐5 reduces endocytic capacity and alters cholesterol distribution in the proximal tubule

Dent disease is a progressive X‐linked disorder affecting the kidney proximal tubule (PT) caused by loss of function of the Cl−/H+ exchanger, CLC‐5. Early symptoms include low molecular weight (LMW) proteinuria resulting from inefficient reabsorption of filtered proteins by the PT. However, the role of CLC‐5 in this process in unclear. Knockout of Clc‐5 in mice recapitulates the LMW proteinuria observed in human disease and causes decreased PT levels of megalin and cubilin, the receptors that bind to and recover filtered proteins. How loss of CLC‐5 leads to reduced receptor expression remains unknown. We used a previously developed opossum kidney (OK) cell culture model that recapitulates morphologic and functional features of the PT in vivo to study the role of Clc‐5 in the endocytic pathway. In Clc‐5 siRNA knockdown (KD) and CRISPR/Cas9 mediated Clc‐5 knockout (KO) cells, there was a significant decrease in endocytic capacity that was rescued by heterologous expression of wild‐type human CLC‐5. Additionally, we used CRISPR/Cas9 technology to generate Clc‐5 knockout mice and confirmed LMW proteinuria in the KO. Heterozygous females also have reduced PT albumin uptake and megalin expression. Previous gene expression studies in Clcn5 KO mice suggest there are alterations in cholesterol and lipid metabolic enzymes, and elevated cholesterol levels have been shown to alter recycling endosome organization and impair fast recycling. We hypothesize that loss of CLC‐5 disrupts cholesterol homeostasis, resulting in reduced recycling and concomitantly increased degradation of megalin. Consistent with this, we observed an accumulation and redistribution of cholesterol in Clc‐5 KD OK cells. We are currently working to quantify cholesterol in Clc‐5 KO OK cells. In female mice with only one functional copy of Clc‐5, we observed a dramatic a change in the distribution of cholesterol in the PT when compared to WT mice. Current studies are focused on quantifying the trafficking kinetics and distribution of megalin in the PT in the absence of CLC‐5 and determining whether altered cholesterol metabolism contributes to the reduced endocytic capacity of the PT and resulting LMW proteinuria in Dent disease.Support or Funding InformationNIH F31 DK121394, R01 DK101484, R01 DK100357, P30 DK079307, and ASN Pre‐Doctoral Fellowship

Cl− and H+ coupling properties and subcellular localizations of wildtype and disease-associated variants of the voltage-gated Cl−/H+ exchanger ClC-5

Dent disease 1 (DD1) is caused by mutations in the CLCN5 gene encoding a voltage-gated electrogenic nCl-/H+ exchanger ClC-5. Using ion-selective microelectrodes and Xenopus oocytes, here we studied Cl-/H+ coupling properties of WT ClC-5 and four DD1-associated variants (S244L, R345W, Q629*, and T657S), along with trafficking and localization of ClC-5. WT ClC-5 had a 2Cl-/H+ exchange ratio at a Vh of +40 mV with a [Cl-]out of 104 mm, but the transport direction did not reverse with a [Cl-]out of 5 mm, indicating that ClC-5-mediated exchange of two Cl- out for one H+ in is not permissible. We hypothesized that ClC-5 and H+-ATPase are functionally coupled during H+-ATPase-mediated endosomal acidification, crucial for ClC-5 activation by depolarizing endosomes. ClC-5 transport that provides three net negative charges appeared self-inhibitory because of ClC-5's voltage-gated properties, but shunt conductance facilitated further H+-ATPase-mediated endosomal acidification. Thus, an on-and-off "burst" of ClC-5 activity was crucial for preventing Cl- exit from endosomes. The subcellular distribution of the ClC-5:S244L variant was comparable with that of WT ClC-5, but the variant had a much slower Cl- and H+ transport and displayed an altered stoichiometry of 1.6:1. The ClC-5:R345W variant exhibited slightly higher Cl-/H+ transport than ClC-5:S244L, but co-localized with early endosomes, suggesting decreased ClC-5:R345W membrane trafficking is perhaps in a fully functional form. The truncated ClC-5:Q629* variant displayed the lowest Cl-/H+ exchange and was retained in the endoplasmic reticulum and cis-Golgi, but not in early endosomes, suggesting the nonsense mutation affects ClC-5 maturation and trafficking.

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

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.

Multicenter study of the clinical features and mutation gene spectrum of Chinese children with Dent disease.

Dent disease is a rare X-linked recessive inherited tubular disease. In this multicenter study, the clinical presentation and genetic background of Chinese children with Dent disease are studied to improve the cognition and diagnostic ability of pediatricians. In this prospective cohort, we described the genotype and phenotype of a national cohort composed of 45 pediatric probands with Dent disease belonging to 45 families from 12 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system. The CLCN5 gene from 32 affected families revealed 28 different mutations. The OCRL gene from 13 affected families revealed 13 different mutations. The incidence of low-molecular-weight proteinuria (LMWP) in both Dent disease type 1 populations and Dent disease type 2 populations was 100.0%; however, the incidence of other manifestations was not high, which was similar to previously reported data. Therefore, LMWP is a key clinical feature that should alert clinicians to the possibility of Dent disease. A high amount of LMWP combined with positive gene test results can be used as the diagnostic criteria for this disease. The diagnostic criteria are helpful in reducing the missed diagnosis of this disease and are beneficial for protecting the renal function of these patients through early diagnosis and early intervention.

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition.

The abnormal deposition of calcium within renal parenchyma, termed nephrocalcinosis, frequently occurs as a result of impaired renal calcium handling. It is closely associated with renal stone formation (nephrolithiasis) as elevated urinary calcium levels (hypercalciuria) are a key common pathological feature underlying these clinical presentations. Although monogenic causes of nephrocalcinosis and nephrolithiasis are rare, they account for a significant disease burden with many patients developing chronic or end-stage renal disease. Identifying underlying genetic mutations in hereditary cases of nephrocalcinosis has provided valuable insights into renal tubulopathies that include hypercalciuria within their varied phenotypes. Genotypes affecting other enzyme pathways, including vitamin D metabolism and hepatic glyoxylate metabolism, are also associated with nephrocalcinosis. As the availability of genetic testing becomes widespread, we cannot be imprecise in our approach to nephrocalcinosis. Monogenic causes of nephrocalcinosis account for a broad range of phenotypes. In cases such as Dent disease, supportive therapies are limited, and early renal replacement therapies are necessitated. In cases such as renal tubular acidosis, a good renal prognosis can be expected providing effective treatment is implemented. It is imperative we adopt a precision-medicine approach to ensure patients and their families receive prompt diagnosis, effective, tailored treatment and accurate prognostic information.

Clinical and genetic analysis of Dent disease with nephrotic range albuminuria in Shaanxi, China.

Clinical and genetic analysis of Dent disease with nephrotic range albuminuria in Shaanxi, China.

Lowe syndrome identified in the offspring of an oocyte donor who was an unknown carrier of a de novo mutation: a case report and review of the literature

BackgroundOculocerebrorenal syndrome of Lowe is an X-linked disorder with very low prevalence in the general population. The OCRL gene encodes the protein phosphatidylinositol 4,5-bisphosphate-5-phosphatase, a lipid phosphatase, located in the trans-Golgi network. Point mutations in the OCRL gene cause Lowe syndrome and Dent disease, which are characterized as a multisystemic disorder. The symptoms of Lowe syndrome are expressed primarily as dysfunction of the eyes, kidneys, and the central nervous system.Case presentationThis report describes a case of a 31-year-old Georgian woman with a de novo pathogenic mutation causing oculocerebrorenal syndrome of Lowe, who was a volunteer in an oocyte donation program for in vitro fertilization purposes, and the outcome of the treatments of this particular donor’s oocyte receivers, describing the implications of the mutation for the children born as a result of the treatments. It raises important medical and ethical issues about the necessity of genetic testing of oocyte donors and the possibility of rare genetic disorders being inherited by the offspring of donors.ConclusionThis particular case indicates the legal, medical, and emotional risks of utilizing donor oocytes from phenotypically healthy women, whose genetic constitution is unknown in terms of being silent carriers of rare diseases. In addition, all the necessary actions were followed; the further examinations that are required are mentioned. The donor and the offspring should be further tested. The remaining cryopreserved embryos should be destroyed or preimplantation genetic testing should be performed before they are utilized. Finally, all the people involved, the treated couples and the donor, alongside her family, should follow genetic and psychological counselling.

Foamy Urine: Is This a Sign of Kidney Disease?

Historically, persistent foamy urine noticed upon voiding is considered a warning sign of kidney disease. Foamy urine is characterized by the appearance and persistence of multiple layers of small to medium bubbles in urine voided into a container, such as a toilet bowl (see [Figure 1][1]). The

Intrafamilial Infection of Helicobacter Pylori: Abnormal Gastric Epithelial Cells, Pedestal-Rich H. Pylori Adherence, and a Gene Mutation in a Child with Protein-Losing Gastroenteropathy

Abstract Helicobacter pylori, one of the most prevalent human pathogens, colonizes the gastric mucosa and is associated with gastric diseases, such as gastritis and peptic ulcers, and is also a bacterial risk factor for gastric cancer. Cytotoxin-associated gene A (CagA) protein, a major virulence factor of H. pylori, is phosphorylated in cells at its Glu-Pro-IIe-Tyr-Ala (EPIYA) motif and is considered to trigger gastric cancer. CagA is classified into two forms, Western CagA with EPIYA-ABC and East Asian CagA with EPIYA-ABD, with the latter associated with a high risk of developing gastric cancer. CagA causes morphological transformation of cells, yielding the “hummingbird” phenotype in AGS cells and possibly membranous pedestals in the gastric epithelium, albeit rarely. H. pylori adherence to the gastric mucosa is not yet fully understood. Here, we describe an intrafamilial infection case of H. pylori, focusing on the gastric epithelium, H. pylori adherence, and a gene mutation in a child with protein-losing gastroenteropathy (characterized by excessive loss of plasma proteins into the gastrointestinal tract). H. pylori, which also infected family members (mother and father), was genetically a single clone with the virulence genes of an East Asian type. The patient’ gastric mucosa exhibited some unique features. Endoscopy revealed the presence of protein plugs on the mucosal surface, which were immunoelectrophoretically similar to serum proteins. Electron microscopy revealed abnormal gastric epithelial cells, totally covered with the secretions or possessing small swollen structures and irregular microvilli. The patient’s H. pylori infection was characterized by frequently occurring thick pedestals, formed along adherent H. pylori. The serum protein level returned to normal and the protein plugs disappeared after the successful eradication of H. pylori, albeit with lag periods for healing. He had a mutation in the OCRL1 gene, associated with Dent disease (asymptomatic proteinuria). Thus, in the patient’s gastric mucosa, we found the abnormal gastric epithelial cells, which may be caused by an OCRL1 mutation or H. pylori, and pedestal-rich H. pylori infection, possibly caused by a higher level of action of CagA in the abnormal epithelial cells. The data suggests a novel H. pylori virulence factor associated with “excessive plasma protein release”.

Dent disease: A window into calcium and phosphate transport.

This review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

A New Estimate of the Glomerular Sieving Coefficient for Retinol-Binding Protein 4 Suggests It Is Not Freely Filtered

A New Estimate of the Glomerular Sieving Coefficient for Retinol-Binding Protein 4 Suggests It Is Not Freely Filtered

Mathematical model of megalin trafficking in differentiated proximal tubule cells and its application in Dent disease

The polarized epithelial cells that comprise the proximal tubule (PT) have a specialized apical endocytic pathway that allows for high‐capacity endocytosis which is necessary to recover essential nutrients and to maintain a protein‐free urine. Megalin, a multi‐ligand receptor at the apical surface of the epithelial cells, binds proteins in the ultrafiltrate and internalizes them via receptor‐mediated endocytosis. Ligands are sorted from receptors in endocytic compartments, and the receptors are recycled back to the surface. The molecular identities of the compartments involved in sorting and recycling in PT cells and the kinetics of megalin trafficking through them are unknown. When endocytosis in the proximal tubule is dysfunctional, tubular proteinuria results. Dent disease, an X‐linked disorder characterized by tubular proteinuria that progresses to renal failure, is caused by mutations in the Cl‐/H+ exchanger CLC‐5. Loss of CLC‐5 has been shown to reduce endocytic uptake and to decrease megalin protein expression without altering mRNA levels. However, the mechanism by which this occurs is unclear. We previously discovered that OK cells cultured under continuous fluid shear stress develop morphological and functional features similar to that of the PT in vivo, including high apical endocytic capacity and increased megalin expression. We used data obtained through biochemical approaches to estimate endocytic and recycling rates and the half‐life of surface megalin in untreated and CLC‐5 knockdown OK cells. These rates were used to construct a simplified model of megalin trafficking in differentiated PT cells. We present an ordinary differential equation (ODE) model of megalin trafficking describing surface and internalized pools of megalin with estimated kinetic parameters. We observed a greater fraction of internalized megalin compared to the surface pool due to an endocytic rate that is much faster than the recycling rate. We have quantified decreases in megalin expression and surface half‐life with loss of CLC‐5 expression. Current and future work includes quantifying alterations in megalin trafficking in CRISPR/Cas9 mediated CLC‐5 KO models and defining the structure and markers of the apical endocytic pathway by quantitative imaging to expand our model to include additional trafficking steps. This model will then be used to predict which steps in megalin trafficking are altered in Dent disease.Support or Funding InformationASN Pre‐Doctoral Fellowship, NIH R01‐DK101484, NIH P30‐DK079307This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Characterization of a new Dent Disease mouse model carrying a pathogenic mutation of ClC‐5

Dent Disease is a rare X‐linked inherited renal proximal disorder characterized by low molecular weight (LMW) proteinuria, hypercalciuria, kidney stones and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl−/H+ exchanger ClC‐5 have been identified in approximately two‐thirds of patients with Dent Disease. ClC‐5 is predominantly expressed in early endosomes of proximal tubules where it optimizes the function of a vacuolar H+ pump to ensure an efficient endocytosis of LMW proteins.We have previously investigated the functional consequences of CLCN5 mutations in heterologous expression systems and shown that 60 % of the mutations lead to a defect in protein folding and processing. As a consequence, the misfolded ClC‐5 are retained within the endoplasmic reticulum (ER) where they could induce ER stress response. Such ER stress might in turn induce oxidative stress in proximal tubule cells. To investigate the consequences of intracellular retention of a misfolded ClC‐5, we created a mouse model carrying the N340K pathogenic mutation.ClC‐5 expression and localization in WT and N340K male mice were studied by Western blot and on kidney sections by immunofluorescence. Daily food, water intake, body weight and urine excretion data were collected in metabolic cages for N340K and WT mice. Urine as well as blood samples were analysed for ions, protein, glucose and creatinine to detect kidney dysfunction as observed in patients with Dent Disease.Mice carrying the N340K mutation displayed ClC‐5 intracellular retention in proximal tubules cells. They showed an increased urinary calcium and glucose excretion and a decreased urinary pH. They also had a severe LMW proteinuria, recapitulating common features of Dent Disease.The present study validates a new Dent Disease mouse model carrying a pathogenic Clcn5 mutation retained in the ER. The potential link between ClC‐5 retention in the ER, ER stress and oxidative stress responses has yet to be demonstrated.Support or Funding InformationPrix “Jeune Chercheur”, Fondation du Rein 2017This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts.

Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α1-microglobulin (α1M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α1M/Cr, α1M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α1M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α1M/Cr of ≥ 120mg/g (> 13.6mg/mmol) creatinine were good screens for Dent disease. CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600mg/g (> 68mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α1M/Cr ≥ 120mg/g (> 13.6mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

C-Terminal Fibroblast Growth Factor-23 Levels in Non-Nutritional Hypophosphatemic Rickets.

Fibroblast growth factor-23 (FGF23) is central to phosphate homeostasis. The author examined if blood levels of FGF23 allow discrimination of classic hypophosphatemic ricketsfrom other causes of non-nutritional rickets with hypophosphatemia. Forty-two children (median age:102 mo) with non-nutritional rickets and hypophosphatemia were clinically classified as having distal renal tubular acidosis (RTA, n = 12), Fanconi syndrome (n = 8), classic hypophosphatemic rickets (n = 11), vitamin D dependent rickets (n = 7) and Dent disease (n = 4). Median blood FGF23 (measured by C-terminal ELISA) concentrations were similar in all groups (P = 0.24). These levels did not correlate with phosphate, tubular maximum for phosphate, calcium, 25-hydroxyvitamin D, creatinine, and parathormone levels. Patients with distal RTA showed variable degree of proximal tubular dysfunction that resolved following alkali supplements. Blood FGF23 levels did not satisfactorily differentiate classic hypophosphatemic rickets from other causes of hypophosphatemic rickets.

Familial Xp11.22 microdeletion including SHROOM4 and CLCN5 is associated with intellectual disability, short stature, microcephaly and Dent disease: a case report

BackgroundTwo interstitial microdeletions Xp11.22 including the CLCN5 and SHROOM4 genes were recently reported in a male individual affected with Dent disease, short stature, psychomotor delay and minor facial anomalies. Dent disease, characterized by a specific renal phenotype, is caused by truncating mutations of CLCN5 in the majority of affected cases.Case presentationHere, we present clinical and molecular findings in a male patient with clinical signs of Dent disease, developmental delay, short stature, microcephaly, and facial dysmorphism. Using molecular karyotyping we identified a hemizygous interstitial microdeletion Xp11.23p.11.22 of about 700 kb, which was inherited from his asymptomatic mother. Among the six deleted genes is CLCN5, which explains the renal phenotype in our patient. SHROOM4, which is partially deleted in this patient, is involved in neuronal development and was shown to be associated with X-linked intellectual disability. This is a candidate gene, the loss of which is thought to be associated with his further clinical manifestations.To rule out mutations in other genes related to intellectual disability, whole exome sequencing was performed. No other pathogenic variants that could explain the phenotypic features, were found.ConclusionWe compared the clinical findings of the patient presented here with the reported case with an Xp11.22 microdeletion including CLCN5 and SHROOM4 and re-defined the phenotypic spectrum associated with this microdeletion.

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease.

Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using OcrlY/− mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from OcrlY/− kidneys. The OcrlY/− mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5–bisphosphate PI(4,5)P2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in OcrlY/− mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in OcrlY/− and Clcn5Y/− mice suggest shared mechanisms in Dent diseases 1 and 2.These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.