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At least 19 recordsLinked to original sources
PubMed2021

Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). METHODS: To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. RESULTS: Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic "second hit" alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2 ; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 17% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another 18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14% of these cysts harbored copy number neutral LOH events, while the other 3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic "second hit" alterations occurred at the same germline mutated PKD1/2 gene. CONCLUSIONS: These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.

Humans↗
PubMed2026

Disruption of Polycystin Ciliary Localization and Channel Function by Autosomal Dominant Polycystic Kidney Disease-Causing Polycystin-1 Variants.

KEY POINTS: We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease. All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function. Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss-of-function variants in polycystin-1 (PC1). METHODS: We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function. RESULTS: We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: ( 1 ) localization of PC1 at the primary cilium or ( 2 ) polycystin ion channel activity. Ciliary localization of a subset of polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels. CONCLUSIONS: This study demonstrated that disruptions in polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for polycystin-targeted therapies in ADPKD.

Polycystic Kidney, Autosomal Dominant↗
PubMed2025

Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort.

PURPOSE: Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). METHODS: We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. RESULTS: Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions. CONCLUSION: A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.

Humans↗
PubMed2026

PKD1 upstream open reading frames affect Polycystin-1 expression and polycystic kidney disease phenotypes.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for 5%-10% of prevalent end-stage kidney failure (ESKD). ADPKD cysts result from a loss of sufficient functional expression of PKD1/Polycystin-1 (PC1) in approximately 80% of families. Kidney disease severity correlates with the extent to which PC1 dosage is reduced below a critical level, and evidence suggests therapeutic benefit from increasing PC1 expression in these conditions. Upstream open reading frame (uORF) translation can reduce translation of a protein's coding sequence. Ribosome profiling data and bioinformatic predictions suggested the presence of conserved PKD1 uORFs, so we sought to explore their biological role. We generated luciferase reporters and two humanized PKD1 5' UTR mouse models with or without single nucleotide edits removing uORF start codons (ΔuORF) to define active uORFs and test their impact on PC1 translation. PKD1 uORF start codons can robustly initiate translation, and ΔuORF conveys a 2-4 fold increase in PC1 protein expression and resultant prevention of kidney cysts in Dnajb11 as well as in Pkd1 missense models. PKD1 uORF1-blocking steric antisense oligonucleotides (ASOs) substantially increase PC1 expression in vitro. PKD1 uORFs play an important role in the low basal expression of WT PKD1, and their inhibition represents an opportunity to therapeutically increase PC1 translation in polycystic kidney and liver disease resulting from reduced dosage of PC1.

Animals↗
PubMed2025

Using Large Genomic Biobanks to Generate Insights into Genetic Kidney Disease.

Chronic kidney disease (CKD) affects approximately 9% of the global population, leading to increased risks of end-stage kidney disease (ESKD), cardiovascular disease (CVD), and mortality. Patients with CKD are a huge burden on health care resources globally. CKD is a complex condition influenced by a combination of genetic, environmental, and traditional risk factors. Family studies have suggested heritability rates for CKD ranging from 30% to 75%, and large genomic biobank studies have proven essential in identifying genes with substantial effects on CKD risk and in capturing cumulative genetic risk through polygenic risk scores. These biobanks are crucial for discovering new genes associated with kidney health and disease, and their growing size enhances the power to detect novel genetic associations. Integrating multi-omics technologies such as transcriptomics, metabolomics, and proteomics further enriches our understanding of CKD, while advanced computational tools continue to expand our insights into genetic data. Polygenic risk scores, derived from hundreds of genetic variants with small effect sizes, can help identify individuals at high risk of CKD. Genomic biobanks offer valuable opportunities for early identification and personalized treatment of monogenic kidney disorders, such as autosomal dominant polycystic kidney disease and Alport syndrome. These biobanks help fill knowledge gaps, particularly in individuals with milder or asymptomatic presentations who are often underrepresented in traditional studies. Expanding genomic biobank efforts globally, especially in diverse populations, is vital to enhancing our understanding of the genetic underpinnings of kidney disease. This review highlights the significant contributions of genomic biobanks to advancing our comprehension of the genetics of CKD.

Humans↗
PubMed2026

Giant Hydronephrosis Secondary to Ureteral Obstruction Imposed by Massive Hepatomegaly in a Patient with Polycystic Liver Disease: A Case Report.

BACKGROUND: Polycystic liver disease is a genetic pathology characterized by the formation of numerous cysts in the liver. This case is notable for the rare presentation of isolated polycystic liver disease leading to secondary obstructive uropathy. Unlike the more common association with autosomal dominant polycystic kidney disease, this patient exhibited no evidence of bilateral polycystic kidney disease; the only renal finding was a solitary simple cyst in the contralateral kidney, considered an incidental finding, highlighting an unusual extrinsic mechanism of urinary tract obstruction due to massive hepatomegaly. In adults, polycystic liver disease often manifests as an extra-renal complication of autosomal dominant polycystic kidney disease. In rare cases, however, it may present solely as autosomal dominant polycystic liver disease without renal involvement. CASE PRESENTATION: In this study, we describe a patient with isolated polycystic liver disease, in whom marked hepatomegaly progressively compressed and displaced the kidney, obstructing the ureter at the pyeloureteral junction. Imaging studies, including abdominal ultrasound and computed tomography, confirmed the extent of cystic involvement and the resulting mass effect. This led to the gradual development of severe hydronephrosis, evident both on palpation and during clinical examination of the abdomen. Hydronephrosis, in turn, exerted pressure on adjacent organs such as the liver, pancreas, stomach, and large vessels, causing symptoms including abdominal distension, dysphagia, gastroesophageal reflux, early satiety, reduced mobility, as well as abdominal and lumbar pain. CONCLUSION: Clinicians should consider the possibility of mass effect complications in patients with isolated polycystic liver disease, as early recognition and intervention may help prevent severe secondary organ dysfunction.

Hydronephrosis↗
PubMed2026

Genetic Testing in Cystic Kidney Disease.

Genomic investigation is playing an increasing role in the management of cystic kidney diseases, reflecting a broader shift toward precision medicine in nephrology. Recent updates to the Kidney Disease Improving Global Outcomes Clinical Practice Guideline emphasize diagnostic genomics as a core component of autosomal dominant polycystic kidney disease care in particular, recognizing its utility across a range of clinical scenarios. Traditionally, diagnosis of autosomal dominant polycystic kidney disease has been clinical, using age-dependent imaging criteria for at-risk individuals via ultrasound and magnetic resonance imaging. Although these imaging modalities have good sensitivity, there are pitfalls in clinical diagnosis, particularly in patients with atypical clinical features, those without family history, or those at a young age. A confirmed genetic diagnosis can guide screening of at-risk family members, inform reproductive decisions, support safe selection of living related kidney donors, and provide the opportunity to use genotype-specific prognostication tools. In addition, as genotype-specific therapies enter the landscape, accurate genotyping will become essential for identifying which patients will benefit from treatment. This narrative review aims to provide a practical approach for the general nephrologist of when to offer genetic testing to patients with cystic kidney disease and outline the technical and genetic counseling considerations in the provision of patient-centered genetic investigation.

Humans↗
PubMed2026

Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease.

Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3'UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 messenger RNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof of concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.

Animals↗
PubMed2026

Prevalence of unruptured intracranial aneurysms according to comorbidities, risk factors, country, and time period: a systematic review and meta-analysis.

BACKGROUND: The incidence of aneurysmal subarachnoid haemorrhage declined between 1980 and 2010, which coincided with a decline in smoking and prevalence of hypertension. We aimed to investigate whether the decrease in subarachnoid haemorrhage incidence is paralleled by declines in unruptured intracranial aneurysm (UIA) prevalence. METHODS: For this systematic review and meta-analysis, we searched Embase, PubMed, and Web of Science for articles published in any language from Jan 1, 2011 to Dec 31, 2025, and reassessed 68 articles published before March 1, 2011 from a 2011 systematic review and meta-analysis. Articles were eligible for inclusion if they used a cross-sectional or case-control design and provided the crude number of participants and those with UIA. We only included studies reporting numbers of UIA separately from ruptured aneurysms and with ten or more patients. Summary data were independently extracted by JD with AZ or CB and conflicts were resolved by GJER. The primary outcome was proportion of participants with UIA. Relative to a hypothetical reference population (mean age 50 years, 50% women, and no comorbidities), age and/or sex-adjusted prevalence ratios (PRs) for regions, comorbidities, and risk ratios (RRs) for female sex, smoking, and hypertension were estimated using generalised linear mixed models. A time trend analysis was done by binomial meta regression using the mid-year of data acquisition. We assessed the certainty of evidence using GRADE. The study was registered with PROSPERO, number CRD420261296728. FINDINGS: Our search screened 4708 studies. 67 reassessed and 95 newly identified articles, reporting on 316 131 participants and 11 822 people with UIAs, were included in our meta-analysis. In the reference population, the estimated prevalence of UIAs was 3·9% (95% CI 3·0-5·1). The prevalence of UIAs in individuals with atherosclerosis was 5·5% (4·7-6·4; 2229 of 40970 participants) and the adjusted PR was 1·3 (95% CI 0·8-2·0) compared with the reference population. For positive family history of aneurysmal subarachnoid haemorrhage (aSAH) or UIA, the UIA prevalence was 7·9% (5·6-11·1; 412 of 4252 participants) and the adjusted PR was 2·4 (0·5-11·2). For connective-tissue disorder, the UIA prevalence was 10·3% (6·5-16·0; 94 of 879 participants) and the adjusted PR was 3·9 (2·0-7·6). For autosomal dominant polycystic kidney disease (ADPKD), the UIA prevalence was 12·8% (9·2-17·6; 293 of 1990 participants) and the adjusted PR was 4·4 (1·5-12·6). RRs were for current smoking 1·4 (1·2-1·6; 798 of 27911 participants), for having hypertension 1·6 (1·5-1·7, 4043 of 83053 participants), and for female sex 1·9 (1·8-2·0; 3415 of 65020 women and 2122 of 76130 men). In studies on healthy individuals with MR angiography or CT angiography as imaging modality, the prevalence in 2016-2022 was 6·6% (6·3-6·8; 2904 of 41191 participants). The adjusted PR was 1·8 (1·1-2·8) for 2016-2022 versus 2002-2015. Prevalence of UIAs of 5 mm or larger was 0·7% (0·6-0·8) in 2002-2015 and 1·4% (1·0-1·9) in 2016-2022. The UIA prevalence did not differ between countries. τ2 showed significant heterogeneity between studies. The certainty of the evidence ranged from very low to moderate. INTERPRETATION: Prevalence of UIA is increasing, particularly over the past two decades. This increase is only in part explained by improved detection of small UIAs and an ageing population, and other factors-such as environmental-are likely involved. Alongside patients with ADPKD and a positive family history of aSAH, patients with connective-tissue disorders had a higher prevalence of UIA than the reference population. Our findings warrant further investigation into the potential benefit of personalised screening and management strategies in groups at high risk for having UIAs. FUNDING: None.

Humans↗
PubMed2026

Small-Molecule Degradation of the MicroRNA-21 Precursor Rescues Pathogenic Pathways in Cellular Models of Fibrosis.

MicroRNAs (miRNAs) are short RNA molecules that bind to target mRNAs, resulting in translational repression and gene silencing. Overexpression of microRNA-21 (miR-21) is associated with various human diseases, including autosomal dominant polycystic kidney disease (ADPKD) and pulmonary fibrosis. In this study, a previously described heterobifunctional molecule, TGP-21-RiboTAC, that degrades the miR-21 precursor (pre-miR-21) in triple-negative breast cancer cells was investigated in polycystic kidney cell lines and a lung fibroblast cell line. In the former, TGP-21-RiboTAC degraded pre-miR-21 and derepressed miR-21's downstream targets, programmed cell death 4 (PDCD4) and peroxisome proliferator-activated receptor alpha (PPARα), known drivers of ADPKD. The heterobifunctional molecule also inhibited cyst growth and rescued the metabolic alterations that occur in ADPKD. In the lung fibroblast cell line, MRC-5, TGP-21-RiboTAC also reduced pre- and mature miR-21 levels, rescued transforming growth factor β (TGF-β)-induced repression of SMAD family member 7 (SMAD7), and inhibited cell invasion. Collectively, these studies demonstrate the potential of targeted RNA degradation as therapeutic agents that retard the development of organ fibrosis.

MicroRNAs↗
PubMed1977

Polycystic kidney disease.

This autosomal dominant disorder usually appears in middle life. The most common findings are proteinuria, abdominal pain and palpable kidneys, followed by hematuria, hypertension, pyuria, uremia and calculi. In 15% of patients, death is due to cerebral aneurysm. Family counseling and the detection of "at risk" family members are important elements of management. Statistically, half of the offspring of one affected parent will have the disease.

Adult↗
PubMed2022

Enhancer and super-enhancer landscape in polycystic kidney disease.

Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super-enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1-mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.

Animals↗
PubMed1978

Renal cysts in premature children: occurrence in a family with polycystic kidney disease.

Discrete but typical renal lesions, probably representing the first stage of familial adult-type polycystic kidney disease, were found in two premature still-born daughters of a woman whose family had many cases of this autosomal dominant disease. Apparently, enough cysts were present to form polycystic kidneys of adult size solely by cyst dilation, without additional cyst formation.

Child↗
PubMed1976

Radiologic features of "adult type" polycystic kidney disease in the neonate.

Two cases are reported of adult type polycystic renal disease (autosomal dominant) presenting in the newborn as a unilateral abdominal mass. The radiographic findings in the involved kidney simulated the ectatic tubules of infantile polycystic disease, yet histologic examination was consistent with the adult variety and both infants had other family members with adult type polycystic kidneys. These cases emphasize some of the ambiguities that exist in the definition and classification of polycystic renal disease.

Adult↗
PubMed1977

Dominantly-inherited polycystic kidneys in infants: association with hypertrophic pyloric stenosis.

Newborn male fraternal twins presented at 10 days of age will bilateral flank masses; intravenous urograms showed polycystic kidney disease. Both babies also had hypertrophic pyloric stenosis (HPS). Their father has radiographic and sonographi findings of previously unsuspected polycystic kidneys and has a history of HPS in infancy. The association of dominantly-inherited polycystic kidneys (DPK) and HPS in this family is probably due to chance. However the authors speculate that the autosomal gene for DPK may occur at one of several loci that carry the genetic liability for HPS, A DISORDER TRANSMITTED BY POLYGENIC INHERITANCE.

Diseases in Twins↗
PubMed1978

Expression of "adult" polycystic renal disease in the fetus and newborn.

The manifestations of "adult" polycystic disease of the kidneys are reported in fetal life and during infancy. At the time of diagnosis, the patients in whom the disorder was detected were a stillborn fetus, a liveborn baby immediately after birth, a neonate at 3 weeks of age, and three infants between 2 1/2 and 4 months of life. In all six cases, who were unrelated, similar implication of other family members was elicited, and in four, parental disease was documented. As expected, the disorder in these families was transmitted in an autosomal dominant fashion. Apart from the youngsters reported here, all the other known patients in the respective families were of adult age. The disease was fatal in all of our patients, with death ensuing (except, of course, in the stillbirth) from hours to weeks after the diagnosis. This report underlines the variability in the age of expression and the mode of presentation of "adult" polycystic kidney disease.

Chromosome Aberrations↗