Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes

Advances in Kidney Disease and Health, Год журнала: 2023, Номер 30(5), С. 397 - 406

Опубликована: Сен. 1, 2023

Язык: Английский

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Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History

Kidney International Reports, Год журнала: 2024, Номер 9(9), С. 2685 - 2694

Опубликована: Июль 16, 2024

Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with kidneys who have positive family history, >90% pathogenic variants in

Язык: Английский

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Quantifying variant contributions in cystic kidney disease using national-scale whole genome sequencing

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(19)

Опубликована: Авг. 27, 2024

BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial in which gene discovery has been led by family-based and candidate studies, an approach that susceptible to ascertainment other biases.METHODSUsing whole-genome sequencing data from 1,209 cases 26,096 ancestry-matched controls participating the 100,000 Genomes Project, we adopted hypothesis-free approaches generate quantitative estimates of risk for each genetic contributor CyKD, across genes, variant types allelic frequencies.RESULTSIn 82.3% cases, qualifying potentially disease-causing rare established was found. There enrichment coding, splicing, structural variants known CyKD with statistically significant gene-based signals COL4A3 (monoallelic) PKHD1. Quantification (with replication separate UK Biobank study) revealed substantially lower associated genes more recently autosomal dominant polycystic disease, odds ratios some below what might usually be regarded as necessary classical Mendelian inheritance. Meta-analysis common did not reveal associations, but suggested this category variation contributes 3%-9% heritability European ancestries.CONCLUSIONBy providing unbiased quantification effects per gene, research suggests all contributors are equally likely manifest trait families. This information may inform testing counseling clinic.

Язык: Английский

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A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis

Kidney International Reports, Год журнала: 2024, Номер 9(7), С. 2209 - 2226

Опубликована: Апрель 15, 2024

Monoallelic variants in the

Язык: Английский

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Phenotypic outcomes of PKD1 compared with non-PKD1 genetically confirmed autosomal dominant polycystic kidney disease

Journal of Nephrology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Язык: Английский

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The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease

Journal of Nephrology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by pathogenic variants in the PKD1 and PKD2 genes. Although type of ADPKD variant can influence severity, rare, hypomorphic have also been reported to modify severity or cause biallelic ADPKD. This study examines whether additional, potentially protein-altering, non-pathogenic contribute phenotypic outcomes. We investigated prevalence protein-altering patients with PKD1-associated The association between outcomes, including progression failure, age at onset hypertension urological events, height-adjusted total volume, predicting renal outcomes PKD (PROPKD) score, were examined. Rare, detected 6% 932 study. presence was associated 4 years earlier failure (hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.18-2.34; P = 0.003), in-trans (n 13/894) showing a greater risk (HR: 1.83; CI 1.00-3.33; 0.049). did not detect statistically significant differences other compared those without variants. In ADPKD, our findings suggest that may severity. These potential clinical implications counselling treating variants, but further investigation such larger, longitudinal cohorts detailed, standardised phenotype data required.

Язык: Английский

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Ciliary Ion Channels in Polycystic Kidney Disease

Cells, Год журнала: 2025, Номер 14(6), С. 459 - 459

Опубликована: Март 19, 2025

Polycystic kidney disease (PKD) is the most common hereditary disorder that disrupts renal function and frequently progresses to end-stage disease. Recent advances have elucidated critical role of primary cilia ciliary ion channels, including transient receptor potential (TRP) cystic fibrosis transmembrane conductance regulator (CFTR), polycystin in pathogenesis PKD. While some channels primarily as chloride (e.g., CFTR), others regulate calcium (Ca+2) homeostasis. These are essential for cellular signaling maintaining normal architecture. Dysregulation these pathways due genetic mutations PKD1 PKD2 leads disrupted Ca+2 cAMP signaling, aberrant fluid secretion, uncontrolled proliferation, resulting tubular cystogenesis. Understanding molecular mechanisms underlying dysfunctions has opened door innovative therapeutic strategies, TRPV4 activators, CFTR inhibitors, calcimimetics, mitigate cyst growth preserve function. This review summarizes current knowledge on roles PKD pathophysiology, highlights interventions targeting identifies future research directions improving patient outcomes.

Язык: Английский

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Autosomal dominant polycystic kidney disease: an overview of recent genetic and clinical advances

Renal Failure, Год журнала: 2025, Номер 47(1)

Опубликована: Апрель 23, 2025

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease, characterized by progressive development of multiple cysts, leading to a gradual decline in function. ADPKD also fourth cause failure (KF) adults. In addition manifestations, associated with various extrarenal features, including liver cardiovascular abnormalities, intracranial aneurysms, and chronic pain significant impact on patients' quality life. While several disease-modifying agents have been tested ADPKD, tolvaptan remains only approved drug US Food Drug Administration. The Mayo Imaging Classification currently practical tool for predicting rate disease progression ADPKD. This review provides comprehensive overview focusing its genetics, pathophysiology, clinical presentation, management, prognostic tools. Advances diagnostic imaging genetic testing improved early detection allowing better classification patients prediction KF. discusses current therapeutic approaches tolvaptan, vasopressin V2-receptor antagonist. Additionally, we address specific issues children pregnant individuals Despite substantial progress understanding there large need additional effective treatments markers provide more personalized care these patients.

Язык: Английский

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The GPCR properties of polycystin-1- A new paradigm

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Ноя. 4, 2022

Polycystin-1 (PC1) is an 11-transmembrane (TM) domain-containing protein encoded by the PKD1 gene, most frequently mutated gene leading to autosomal dominant polycystic kidney disease (ADPKD). This large (> 462 kDal) has a complex posttranslational maturation process, with over five proteolytic cleavages having been described, and found at multiple cellular locations. The initial description of binding activation heterotrimeric Gαi/o juxtamembrane region PC1 cytosolic C-terminal tail (C-tail) more than 20 years ago opened door investigations, controversies, into PC1’s potential function as novel G protein-coupled receptor (GPCR). Subsequent biochemical cellular-based assays supported ability C-tail bind numerous members Gα family either inhibit or activate protein-dependent pathways involved in regulation ion channel activity, transcription factor activation, apoptosis. More recent work demonstrated essential role for PC1-mediated preventing cyst development; however, mechanisms which regulates activity continue be discovered. Similarities between adhesion class 7-TM GPCRs, notably conserved GPCR proteolysis site (GPS) before first TM domain, undergoes autocatalyzed cleavage, suggest signaling. article reviews evidence supporting GPCR-like functions their relevance cystic disease, discusses involvement GPS cleavage ligands regulating function, explores connections properties polycystin receptor-channel complex.

Язык: Английский

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Cystic Kidney Diseases in Children and Adults: Differences and Gaps in Clinical Management

Seminars in Nephrology, Год журнала: 2023, Номер 43(4), С. 151434 - 151434

Опубликована: Июль 1, 2023

Язык: Английский

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