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BMC Nephrology Jul 2023Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease (CKD) that requires dialysis. Knowing geographical...
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease (CKD) that requires dialysis. Knowing geographical clusters can be critical for early diagnosis, progression control, and genetic counseling. The objective was to establish the prevalence, geographic location, and ethnic groups of patients with ADPKD who underwent dialysis or kidney transplant in Colombia between 2015 and 2019.
METHODS
We did a cross-sectional study with data from the National Registry of Chronic Kidney Disease (NRCKD) managed by the High-Cost Diseases Fund (Cuenta de Alto Costo [CAC] in Spanish) between July 1, 2015, and June 30, 2019. We included Colombian population with CKD with or without renal replacement therapy (RRT) due to ADPKD. Crude and adjusted prevalence rates were estimated by state and city.
RESULTS
3,339 patients with ADPKD were included, period prevalence was 9.81 per 100,000 population; there were 4.35 cases of RRT per 100,000 population, mean age of 52.58 years (± 13.21), and 52.78% women. Seventy-six patients were Afro-Colombians, six were indigenous, and one Roma people. A total of 46.07% began scheduled dialysis. The highest adjusted prevalence rate was in Valle del Cauca (6.55 cases per 100,000 population), followed by Risaralda, and La Guajira. Regarding cities, Cali had the highest prevalence rate (9.38 cases per 100,000 population), followed by Pasto, Medellin, and Bucaramanga.
CONCLUSIONS
ADPKD prevalence is lower compared to Europe and US; some states with higher prevalence could be objective to genetic prevalence study.
Topics: Humans; Female; Middle Aged; Male; Polycystic Kidney, Autosomal Dominant; Colombia; Renal Dialysis; Cross-Sectional Studies; Renal Insufficiency, Chronic
PubMed: 37460967
DOI: 10.1186/s12882-023-03266-3 -
BMC Genomics Jul 2023Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic multisystem disease caused primarily by mutations in the PKD1 gene or PKD2 gene. There is...
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic multisystem disease caused primarily by mutations in the PKD1 gene or PKD2 gene. There is increasing evidence that some of these variants, which are described as missense, synonymous or nonsense mutations in the literature or databases, may be deleterious by affecting the pre-mRNA splicing process.
RESULTS
This study aimed to determine the effect of these PKD1 and PKD2 variants on exon splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 19 candidate single nucleotide alterations, 11 variants distributed in PKD1 (c.7866C > A, c.7960A > G, c.7979A > T, c.7987C > T, c.11248C > G, c.11251C > T, c.11257C > G, c.11257C > T, c.11346C > T, and c.11393C > G) and PKD2 (c.1480G > T) were identified to result in exon skipping.
CONCLUSIONS
We confirmed that 11 variants in the gene of PKD1 and PKD2 affect normal splicing by interfering the recognition of classical splicing sites or by disrupting exon splicing enhancers and generating exon splicing silencers. This is the most comprehensive study to date on pre-mRNA splicing of exonic variants in ADPKD-associated disease-causing genes in consideration of the increasing number of identified variants in PKD1 and PKD2 gene in recent years. These results emphasize the significance of assessing the effect of exon single nucleotide variants in ADPKD at the mRNA level.
Topics: Humans; Exons; Mutation; Polycystic Kidney, Autosomal Dominant; RNA Precursors; RNA Splicing; TRPP Cation Channels; Pyruvate Dehydrogenase Acetyl-Transferring Kinase
PubMed: 37468838
DOI: 10.1186/s12864-023-09444-9 -
Clinical Science (London, England :... Aug 2023Polycystic kidney disease (PKD) is a developmental disorder, which either manifests in early childhood or later in life, depending on the genetic mutation one harbors....
Polycystic kidney disease (PKD) is a developmental disorder, which either manifests in early childhood or later in life, depending on the genetic mutation one harbors. The mechanisms of cyst initiation are not well understood. Increasing literature is now suggesting that Notch signaling may play a critical role in PKD. Activation of Notch signaling is important during nephrogenesis and slows down after development. Deletion of various Notch molecules in the cap mesenchyme leads to formation of cysts and early death in mice. A new study by Belyea et al. has now found that cells of renin lineage may link Notch expression and cystic kidney disease. Here, we use our understanding of Notch signaling and PKD to speculate about the significance of these interactions.
Topics: Child, Preschool; Mice; Humans; Animals; Renin; Polycystic Kidney Diseases; Signal Transduction; Mutation; Polycystic Kidney, Autosomal Dominant; Kidney
PubMed: 37553961
DOI: 10.1042/CS20230023 -
Journal of the American Society of... Sep 2023Heterozygous DNAJB11 mutation carriers manifest with small cystic kidneys and renal failure in adulthood. Recessive cases with prenatal cystic kidney dysplasia were...
SIGNIFICANCE STATEMENT
Heterozygous DNAJB11 mutation carriers manifest with small cystic kidneys and renal failure in adulthood. Recessive cases with prenatal cystic kidney dysplasia were recently described. Our in vitro and mouse model studies investigate the proposed disease mechanism as an overlap of autosomal-dominant polycystic kidney disease and autosomal-dominant tubulointerstitial kidney disease pathogenesis. We find that DNAJB11 loss impairs cleavage and maturation of the autosomal-dominant polycystic kidney disease protein polycystin-1 (PC1) and results in dosage-dependent cyst formation in mice. We find that Dnajb11 loss does not activate the unfolded protein response, drawing a fundamental contrast with the pathogenesis of autosomal-dominant tubulointerstitial kidney disease. We instead propose that fibrosis in DNAJB11 -kidney disease may represent an exaggerated response to polycystin-dependent cysts.
BACKGROUND
Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo . DNAJB11 encodes an Hsp40 cochaperone in the endoplasmic reticulum: the site of maturation of the ADPKD polycystin-1 (PC1) protein and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases.
METHODS
We used germline and conditional alleles to model Dnajb11 -kidney disease in mice. In complementary experiments, we generated two novel Dnajb11-/- cell lines that allow assessment of PC1 C-terminal fragment and its ratio to the immature full-length protein.
RESULTS
Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11-/- mice are live-born at below the expected Mendelian ratio and die at a weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mouse models show no evidence of UPR activation or cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis.
CONCLUSIONS
DNAJB11 -kidney disease is on the spectrum of ADPKD phenotypes with a PC1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.
Topics: Mice; Animals; Polycystic Kidney, Autosomal Dominant; TRPP Cation Channels; Kidney; Polycystic Kidney Diseases; Disease Models, Animal; Renal Insufficiency; Cysts
PubMed: 37332102
DOI: 10.1681/ASN.0000000000000164 -
Science Bulletin Jun 2024Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein...
Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein polycystin-1 (PC1, encoded by Pkd1) is critical for bone formation. However, the role of PC1 in bone resorption is unknown. Here, we found that PC1 directly regulates osteoclastogenesis and bone resorption. The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts, decreased bone resorption, and increased bone mass. A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease, which is mainly caused by loss-of-function mutation of the PKD1 gene, is associated with a lower risk of hip fracture than those with other chronic kidney diseases. Moreover, mice with osteoclast-specific knockout of Pkd1 showed complete resistance to unloading-induced bone loss. A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass. Pharmacological regulation of the PC1-TAZ axis alleviated unloading- and estrogen deficiency- induced bone loss. Thus, the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.
Topics: Animals; TRPP Cation Channels; Bone Resorption; Osteoclasts; Mice; Osteogenesis; Mice, Knockout; Humans; Osteoporosis; Polycystic Kidney, Autosomal Dominant; Male; Female; Adaptor Proteins, Signal Transducing
PubMed: 38760248
DOI: 10.1016/j.scib.2024.04.044 -
The British Journal of Ophthalmology Sep 2023Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic... (Review)
Review
Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin ()-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).Autosomal dominant RP represents 15%-25% of all RP, with accounting for 20%-30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with -adRP would typically become severely visually impaired at an age 2-3 times older than in X-linked -RP.Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes , and among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here.
Topics: Humans; Child, Preschool; Retinitis Pigmentosa; Rhodopsin; Retina; Cone-Rod Dystrophies; Genotype; Mutation; Eye Proteins; Bestrophins
PubMed: 36038193
DOI: 10.1136/bjo-2022-321903 -
Frontiers in Genome Editing 2024Epigenetics refers to the molecules and mechanisms that modify gene expression states without changing the nucleotide context. These modifications are what encode the... (Review)
Review
Epigenetics refers to the molecules and mechanisms that modify gene expression states without changing the nucleotide context. These modifications are what encode the cell state during differentiation or epigenetic memory in mitosis. Epigenetic modifications can alter gene expression by changing the chromatin architecture by altering the affinity for DNA to wrap around histone octamers, forming nucleosomes. The higher affinity the DNA has for the histones, the tighter it will wrap and therefore induce a heterochromatin state, silencing gene expression. Several groups have shown the ability to harness the cell's natural epigenetic modification pathways to engineer proteins that can induce changes in epigenetics and consequently regulate gene expression. Therefore, epigenetic modification can be used to target and treat disorders through the modification of endogenous gene expression. The use of epigenetic modifications may prove an effective path towards regulating gene expression to potentially correct or cure genetic disorders.
PubMed: 38510848
DOI: 10.3389/fgeed.2024.1304110 -
Genes Dec 2023Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic...
Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (, , , , , , , and ) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway. Recently, was recognized as a novel Noonan syndrome gene with autosomal recessive inheritance, and only four families have been described to date. Here, we report the first Italian case, a one-year-old child with left ventricular hypertrophy, moderate pulmonary valve stenosis, and atrial septal defect, with a clinical suspicion of RASopathy supported by the presence of typical Noonan-like facial features and short stature. Exome sequencing identified a novel homozygous loss-of-function variant in the exon 3 of (NM_181784.3:c.325del; p.Arg109Glufs*7), likely causing nonsense-mediated decay. Our results and the presented clinical data may help us to further understand and dissect the genetic heterogeneity of Noonan syndrome.
Topics: Humans; Infant; Cardiomyopathy, Hypertrophic; Causality; Dwarfism; Exons; Noonan Syndrome; Repressor Proteins; Transcription Factors
PubMed: 38254922
DOI: 10.3390/genes15010032 -
Current Issues in Molecular Biology Sep 2023This review highlights the effect of carcinomas on the results of the examination of autosomal genetic traits for identification and paternity tests when carcinoid... (Review)
Review
This review highlights the effect of carcinomas on the results of the examination of autosomal genetic traits for identification and paternity tests when carcinoid tissue is the only source and no other samples are available. In DNA typing or genetic fingerprinting, variable elements are isolated and identified within the base pair sequences that form the DNA. The person's probable identity can be determined by analysing nucleotide sequences in particular regions of DNA unique to everyone. Genetics plays an increasingly important role in the risk stratification and management of carcinoma patients. The available information from previous studies has indicated that in some incidents, including mass disasters and crimes such as terrorist incidents, biological evidence may not be available at the scene of the accident, except for some unknown human remains found in the form of undefined human tissues. If these tissues have cancerous tumours, it may affect the examination of the genetic traits derived from these samples, thereby resulting in a failure to identify the person. Pathology units, more often, verify the identity of the patients who were diagnosed with cancer in reference to their deceased tumorous relatives. Genetic fingerprinting (GF) is also used in paternity testing when the alleged parent disappeared or died and earlier was diagnosed and treated for cancer.
PubMed: 37754244
DOI: 10.3390/cimb45090460 -
Annals of Human Genetics Jan 2024Autosomal recessive polycystic kidney disease is an early onset inherited hepatorenal disorder affecting around 1 in 20,000 births with no approved specific therapies.... (Review)
Review
Autosomal recessive polycystic kidney disease is an early onset inherited hepatorenal disorder affecting around 1 in 20,000 births with no approved specific therapies. The disease is almost always caused by variations in the polycystic kidney and hepatic disease 1 gene, which encodes fibrocystin (FC), a very large, single-pass transmembrane glycoprotein found in primary cilia, urine and urinary exosomes. By comparison to proteins involved in autosomal dominant PKD, our structural and molecular understanding of FC has lagged far behind such that there are no published experimentally determined structures of any part of the protein. Bioinformatics analyses predict that the ectodomain contains a long chain of immunoglobulin-like plexin-transcription factor domains, a protective antigen 14 domain, a tandem G8-TMEM2 homology region and a sperm protein, enterokinase and agrin domain. Here we review current knowledge on the molecular function of the protein from a structural perspective.
Topics: Humans; Polycystic Kidney, Autosomal Recessive; Receptors, Cell Surface; RNA; Transcription Factors; Sperm Proteins; Protein Conformation
PubMed: 37905714
DOI: 10.1111/ahg.12535