Genotype Phenotype Correlation in Dent Disease 2 and Review of the Literature: OCRL Gene Pleiotropism or Extreme Phenotypic Variability of Lowe Syndrome?

Dent disease is a rare X-linked renal tubulopathy due to CLCN5 and OCRL (DD2) mutations. OCRL 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 OCRL 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 OCRL 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.

Bartter-Like Syndrome as the Initial Presentation of Dent Disease 1: A Case Report

Dent disease is a rare genetic disease characterized by low-molecular-weight proteinuria. Dent disease with Bartter-like syndrome is rare and can easily be misdiagnosed and mistreated. Herein, we report a case of Dent disease 1 with Bartter-like syndrome as the initial manifestation. The patient was admitted to The Second Xiangya Hospital of Central South University due to polydipsia, polyuria, and weakness of both lower limbs at 2 years of age. Laboratory tests showed that serum sodium, potassium and chlorine levels were low, while serum creatinine levels were normal. The calcium level in the urine was normal. The patient was initially diagnosed with Bartter syndrome, and despite medical interventions, he eventually developed chronic kidney disease stage 4 at 13 years of age. To determine the cause, the patient was recommended to undergo genetic testing, which showed a CLCN5 gene c. 941C > T mutation (p.S314L), and was finally diagnosed as Dent disease 1. The clinical manifestations of Dent disease are complex and diverse. For patients with atypical clinical manifestations or unsatisfactory therapeutic effects, genetic testing is recommended.

Auto-inhibitory intramolecular S5/S6 interaction in the TRPV6 channel regulates breast cancer cell migration and invasion

TRPV6, a Ca-selective channel, is abundantly expressed in the placenta, intestine, kidney and bone marrow. TRPV6 is vital to Ca homeostasis and its defective expression or function is linked to transient neonatal hyperparathyroidism, Lowe syndrome/Dent disease, renal stone, osteoporosis and cancers. The fact that the molecular mechanism underlying the function and regulation of TRPV6 is still not well understood hampers, in particular, the understanding of how TRPV6 contributes to breast cancer development. By electrophysiology and Ca imaging in Xenopus oocytes and cancer cells, molecular biology and numerical simulation, here we reveal an intramolecular S5/S6 helix interaction in TRPV6 that is functionally autoinhibitory and is mediated by the R532:D620 bonding. Predicted pathogenic mutation R532Q within S5 disrupts the S5/S6 interaction leading to gain-of-function of the channel, which promotes breast cancer cell progression through strengthening of the TRPV6/PI3K interaction, activation of a PI3K/Akt/GSK-3β cascade, and up-regulation of epithelial-mesenchymal transition and anti-apoptosis.

MO048PATHOGENIC VARIANTS IN CHLORIDE VOLTAGE-GATED CHANNEL 5 (CLCN5), ASSOCIATED WITH DENT DISEASE TYPE 1, SHOULD BE CONSIDERED IN END-STAGE KIDNEY DISEASE OF UNKNOWN AETIOLOGY

Background and Aims Hemizygous variants in chloride voltage-gated channel 5 (CLCN5) on chromosome Xp11.22 cause Dent disease type 1, characterised by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. We describe a truncating pathogenic variant in two brothers presenting with end-stage kidney disease (ESKD) and no evidence of nephrolithiasis or nephrocalcinosis. Method Two white British brothers presented to a different regional centre over 20 years ago with ESKD of unknown aetiology. The UK 100,000 Genomes Project provided a unique opportunity to make a molecular diagnosis using whole-genome sequencing linked to clinical records. Results The older brother presented with ESKD aged 23 with bilateral small kidneys and no evidence of nephrolithiasis or nephrocalcinosis on ultrasound. He had various musculoskeletal pains, 'cutaneous ectopic calcification' and secondary hyperparathyroidism, all of which improved post parathyroidectomy. Investigation of his 17-year-old brother for consideration of kidney transplant donation revealed progressive chronic kidney disease (CKD), microscopic haematuria, proteinuria (3g/24hours) and hypokalaemia. There was no nephrocalcinosis or renal calculi on ultrasound or cystoscopy. Renal biopsy showed tubulointerstitial changes with patchy fibrosis and marked chronic inflammatory cell infiltrates. He had a history of enuresis, polydipsia, delayed bone age and general developmental delay. ESKD by the age of 22 was complicated by hypertension and hyperparathyroidism requiring parathyroidectomy. Right knee pain with 'unusual osteochondral abnormality' on MRI resulted in a supracondylar femoral osteotomy. Early serum and urine biochemistry results were not available. A hemizygous nonsense variant p.Arg417Ter in CLCN5 was identified by whole-genome sequencing via the 100,000 Genomes Project. Sanger sequencing at the Wessex Regional Genetics Laboratory confirmed this. This variant was predicted to be protein-truncating, was absent in the genome aggregation database (gnomAD) and equivalent to a variant associated with Dent disease in other patients therefore classified as a class 5 pathogenic variant according to ACMG guidelines. Three male children with Dent disease have previously been reported with the pathogenic variant p.Arg347Ter. A seven and a twelve year old from two different families in Japan had microscopic haematuria, proteinuria, elevated β2-microglobulin and normal renal function. The twelve-year-old had mild hypercalciuria, but neither had a history of nephrolithiasis or nephrocalcinosis. A four-year-old Turkish boy manifested hypophosphataemia, nephrolithiasis and nephrocalcinosis. Unusually for Dent disease, he also had hypokalaemic hypochloraemic metabolic alkalosis and hyper-reninaemic hyperaldosteronism more characteristic of Bartter syndrome, but with elevated β2-microglobulin more typical of Dent disease. None of these cases had CKD but were all reported at a very young age. Conclusion Approximately 15% of patients with ESKD in Europe have an unknown aetiology. Dent disease has a variable phenotype and screening of patients for low molecular weight proteinuria such as β2-microglobulin is not routinely performed. Dent disease type 1 should be considered in patients presenting with unexplained renal failure even without typical clinical features.

Correction to: Functional analysis of suspected splicing variants in CLCN5 gene in Dent disease 1

A correction to this paper has been published: https://doi.org/10.1007/s10157-021-02041-8