Type of PKD1 mutation influences renal outcome in ADPKD.
01 Jun 2013-Journal of The American Society of Nephrology (American Society of Nephrology)-Vol. 24, Iss: 6, pp 1006-1013
TL;DR: It is confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated withPKD1 mutations, and the type of PKD1 mutation, but not its position, correlated strongly with renal survival.
Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.
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Emory University1, University of Zurich2, University of Erlangen-Nuremberg3, University Medical Center Groningen4, Juntendo University5, Hennepin County Medical Center6, University Health Network7, Tufts University8, Université catholique de Louvain9, University of Colorado Denver10, Autonomous University of Barcelona11, Mayo Clinic12, University of Maryland, Baltimore13, University College London14
TL;DR: This review summarized areas of consensus, gaps in knowledge, and research and health-care priorities related to diagnosis; monitoring of kidney disease progression; management of hypertension, renal function decline and complications; end-stage renal disease; extrarenal complications; and practical integrated patient support that are summarized in this review.
413 citations
TL;DR: A longitudinal mixed regression model to predict eGFR decline showed that log2HtTKV and age significantly interacted with time in typical patients, but not in atypical patients.
Abstract: The rate of renal disease progression varies widely among patients with autosomal dominant polycystic kidney disease (ADPKD), necessitating optimal patient selection for enrollment into clinical trials. Patients from the Mayo Clinic Translational PKD Center with ADPKD (n=590) with computed tomography/magnetic resonance images and three or more eGFR measurements over ≥6 months were classified radiologically as typical (n=538) or atypical (n=52). Total kidney volume (TKV) was measured using stereology (TKVs) and ellipsoid equation (TKVe). Typical patients were randomly partitioned into development and internal validation sets and subclassified according to height-adjusted TKV (HtTKV) ranges for age (1A–1E, in increasing order). Consortium for Radiologic Imaging Study of PKD (CRISP) participants (n=173) were used for external validation. TKVe correlated strongly with TKVs, without systematic underestimation or overestimation. A longitudinal mixed regression model to predict eGFR decline showed that log2HtTKV and age significantly interacted with time in typical patients, but not in atypical patients. When 1A–1E classifications were used instead of log2HtTKV, eGFR slopes were significantly different among subclasses and, except for 1A, different from those in healthy kidney donors. The equation derived from the development set predicted eGFR in both validation sets. The frequency of ESRD at 10 years increased from subclass 1A (2.4%) to 1E (66.9%) in the Mayo cohort and from 1C (2.2%) to 1E (22.3%) in the younger CRISP cohort. Class and subclass designations were stable. An easily applied classification of ADPKD based on HtTKV and age should optimize patient selection for enrollment into clinical trials and for treatment when one becomes available.
402 citations
06 Dec 2018
TL;DR: An overview of the current knowledge of PKD and its treatment can be found in this paper, where the authors provide an overview of existing knowledge about the pathogenesis and treatment of polycystic kidney disease.
Abstract: Cystic kidneys are common causes of end-stage renal disease, both in children and in adults. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are cilia-related disorders and the two main forms of monogenic cystic kidney diseases. ADPKD is a common disease that mostly presents in adults, whereas ARPKD is a rarer and often more severe form of polycystic kidney disease (PKD) that usually presents perinatally or in early childhood. Cell biological and clinical research approaches have expanded our knowledge of the pathogenesis of ADPKD and ARPKD and revealed some mechanistic overlap between them. A reduced 'dosage' of PKD proteins is thought to disturb cell homeostasis and converging signalling pathways, such as Ca2+, cAMP, mechanistic target of rapamycin, WNT, vascular endothelial growth factor and Hippo signalling, and could explain the more severe clinical course in some patients with PKD. Genetic diagnosis might benefit families and improve the clinical management of patients, which might be enhanced even further with emerging therapeutic options. However, many important questions about the pathogenesis of PKD remain. In this Primer, we provide an overview of the current knowledge of PKD and its treatment.
332 citations
TL;DR: Overall, it is shown that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.
Abstract: Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 (∼85% and ∼15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations. After screening, 7%-10% of ADPKD-affected and ∼50% of ADPLD-affected families were genetically unresolved (GUR), suggesting further genetic heterogeneity of both disorders. Whole-exome sequencing of six GUR ADPKD-affected families identified one with a missense mutation in GANAB, encoding glucosidase II subunit α (GIIα). Because PRKCSH encodes GIIβ, GANAB is a strong ADPKD and ADPLD candidate gene. Sanger screening of 321 additional GUR families identified eight further likely mutations (six truncating), and a total of 20 affected individuals were identified in seven ADPKD- and two ADPLD-affected families. The phenotype was mild PKD and variable, including severe, PLD. Analysis of GANAB-null cells showed an absolute requirement of GIIα for maturation and surface and ciliary localization of the ADPKD proteins (PC1 and PC2), and reduced mature PC1 was seen in GANAB(+/-) cells. PC1 surface localization in GANAB(-/-) cells was rescued by wild-type, but not mutant, GIIα. Overall, we show that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.
302 citations
Cites background from "Type of PKD1 mutation influences re..."
...613095]).(7) Larger kidneys (measured by the heightadjusted, MRI-determined total kidney volume [htTKV]) and an earlier decline in renal function (measured by the estimated glomerular filtration rate [eGFR]) are also associated with PKD1 (MIM: 173900)....
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TL;DR: An improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets.
Abstract: Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.
267 citations
Cites background from "Type of PKD1 mutation influences re..."
...Recently, up to 50% of nontruncating changes have been suggested to be hypomorphic, resulting in ESRD at 55 years in patients with truncating PKD1 mutations and 67 years for those with nontruncating mutations (26, 38)....
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References
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TL;DR: MutationTaster allows the efficient filtering of NGS data for alterations with high disease-causing potential and provides Perl scripts that can process data from all major platforms (Roche 454, Illumina Genome Analyzer and ABI SOLiD).
Abstract: (simple_aae) or at alterations causing complex changes in the amino acid sequence (complex_aae). To train the classifier, we generated a dataset with all available and suitable common polymorphisms and known diseasecausing mutations extracted from common databases and the literature. We cross-validated the classifier five times including all three prediction models and obtained an overall accuracy of 91.1 ± 0.1%. We also compared MutationTaster with similar applications (Panther3, Pmut4, PolyPhen and PolyPhen-2 (ref. 5) and ‘screening for non-acceptable polymorphisms’ (SNAP)6) and analyzed the identical 1,000 disease-linked mutations and 1,000 polymorphisms with all programs. For this comparison, we used only alterations causing single amino acid exchanges. MutationTaster performed best in terms of accuracy and speed (Table 1). A description of all training and validation procedures and detailed statistics are available in Supplementary Methods. MutationTaster can be used via an intuitive web interface to analyze single mutations as well as in batch mode. To streamline and to standardize the analysis of NGS data, we provide Perl scripts that can process data from all major platforms (Roche 454, Illumina Genome Analyzer and ABI SOLiD). MutationTaster hence allows the efficient filtering of NGS data for alterations with high disease-causing potential (see Supplementary Methods for an example). Present limitations of the software comprise its inability to analyze insertion-deletions greater than 12 base pairs and alterations spanning an intron-exon border. Also, analysis of non-exonic alterations is restricted to Kozak consensus sequence, splice sites and poly(A) signal. We will add tests for other sequence motifs in the near future. MutationTaster is available at http://www.mutationtaster.org/.
2,628 citations
TL;DR: A World Wide Web server is presented to predict the effect of an nsSNP on protein structure and function and the dependence of selective pressure on the structural and functional properties of proteins is studied.
Abstract: Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.
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TL;DR: This work has updated SIFT’s genome-wide prediction tool since the last publication in 2009, and added new features to the insertion/deletion (indel) tool.
Abstract: The Sorting Intolerant from Tolerant (SIFT) algorithm predicts the effect of coding variants on protein function. It was first introduced in 2001, with a corresponding website that provides users with predictions on their variants. Since its release, SIFT has become one of the standard tools for characterizing missense variation. We have updated SIFT’s genome-wide prediction tool since our last publication in 2009, and added new features to the insertion/deletion (indel) tool. We also show accuracy metrics on independent data sets. The original developers have hosted the SIFT web server at FHCRC, JCVI and the web server is currently located at BII. The URL is http://sift-dna.org (24 May 2012, date last accessed).
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TL;DR: A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning and it has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD 1, and the family of voltage-activated calcium channels.
Abstract: A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.
1,336 citations
TL;DR: Partial sequence analysis of the PKD1 transcript shows that it encodes a novel protein whose function is at present unknown, and a chromosome translocation associated with ADPKD that disrupts a gene (PBP) encoding a 14 kb transcript in thePKD1 candidate region is identified.
743 citations