scholarly journals Aberrant Splicing in the PKD2 Gene as a Cause of Polycystic Kidney Disease

1999 ◽  
Vol 10 (11) ◽  
pp. 2342-2351 ◽  
Author(s):  
DAVID M. REYNOLDS ◽  
TOMOHITO HAYASHI ◽  
YIQIANG CAI ◽  
BARBERA VELDHUISEN ◽  
TERRY J. WATNICK ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Splice Variants ◽  
Missense Variant ◽  
Single Base Substitution ◽  
Base Substitution ◽  
Polycystic Kidney ◽  
Single Base ◽  
Functional Studies ◽  
Pathogenic Variants

Abstract. It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing “second hits” in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2.

MO044TARGETED NEXT GENERATION SEQUENCING AND MULTIDISCIPLINARY APPROACH IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE, ALPORT DISEASE AND FAMILIAL HAEMATURIA: GENETIC SPECTRUM AND CLINICAL UTILITY IN A SPANISH COHORT

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Isabel Galan Carrillo ◽  
Liliana Galbis ◽  
Víctor Martínez Jiménez ◽  
Juan David Castro ◽  
Fernanda Ramos ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Utility ◽  
Multidisciplinary Approach ◽  
Kidney Biopsy ◽  
Kidney Diseases ◽  
Polycystic Kidney ◽  
Pathogenic Variants ◽  
Generation Sequencing

Abstract Background and Aims Autosomal Polycystic kidney Disease (ADPKD; ORPHA 730), Alport Syndrome (AS; ORPHA 63) and Familial Haematuria (FH) are the most frequent inherited kidney diseases. Next-generation Sequencing (NGS) has facilitated their molecular identification. A multidisciplinary team from four hospitals, with nephrologists, pediatricians, and clinical and molecular geneticists, has been formed in the Spanish region of Murcia (1.5 million inhabitants) with the lab implementation of NGS. Our aim is to evaluate the genetic spectrum in AS, FH and ADPKD and the clinical utility of this comprehensive approach. Method During 1-year activity, 114 individuals with diagnostic suspicion of ADPKD, AS or FH have been evaluated by a coordinated clinical protocol with periodic cases discussions. A customized Agilent panel was designed to capture 113 genes associated with several genetic diseases, including some related to PKD, AS or Familial Haematuria (FH): PKD1, PKD2, PKHD1, HNF1β, COL4A1, COL4A3, COL4A4 and COL4A5. Interpretation of sequence variants was performed according to the American College of Medical Genetics and Genomics (ACMG) Guidelines. Sanger sequencing was performed to confirm variants identified by NGS and to segregate them in the families. Exon 1 of PKD1 gene was also sequenced by Sanger method, due to the suboptimal capture of this region by NGS. Results We detected genetic variants in 63 patients (55.3%), pathogenic or probably pathogenic variants in 54 (47.8%). 31 patients had a variant in AS associated genes: 10 in COL4A3, 18 in COL4A4, 2 in COL4A1 and 1 in COL4A5. There were 13 pathogenic variants, 12 probably pathogenic variants and 6 variants of uncertain clinical significance (VUCS). Among them, 27 had an AD inheritance, 1 AR and 3 were sporadic. All the patients with any variant had microhaematuria, a 68% had also proteinuria, and mean eGFR at diagnostic was 63.79±21 ml/min/1.73m2. 61% had auditory disturbances and 11% ophthalmologic alterations. 4 of them had underwent kidney biopsy previously, but 3 were not adequately diagnosed, so they were reclassified after the molecular diagnosis. In total, 16 kidney biopsies were avoided by the genetic diagnosis. On the other hand, 29 patients had a variant in the ADPKD associated genes: 24 in PKD1 and 5 in PKD2. There were 20 pathogenic variants and 4 probably pathogenic variants, and their inheritance was confirmed AD in 27 patients, whereas new sporadic mutations were identified in 2 patients. 22 patients had big or enormous kidneys on sonography, although 7 had normal size. Hepatic cysts were present on 5%. 19 patients had hypertension, with a mean age of diagnosis of 47±14 years. Additionally, 1 patient was diagnosed on AR polycystic disease with homozygosity PKHD1 pathogenic variant. Among all the scope, familial history was clearly present in 43 patients, uncertain in 11, and not present in 9 patients. Conclusion The multidisciplinary approach to hereditary kidney diseases, with the active participation of nephrologists and clinical geneticists, has allowed a molecular diagnostic yield of 48% among patients with AS and ADPKD, employing NGS technology. This has led to a quicker diagnostic result in our region, the reclassification of some patient’s diagnosis, a decrease in invasive diagnostic procedures (such as kidney biopsy) and the correspondent adverse events and cost savings. Additionally, the AD inheritance pattern in AS has been confirmed as the most frequent in the region. The active participation of nephrologists in genomic medicine teams results in a better characterization of the hereditary kidney diseases, helping in the genetic variant interpretation and management of these patients and their families.

Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between WT1 and PKD1

2020 ◽  
pp. jmedgenet-2019-106633
Author(s):  
Johannes Münch ◽  
Karin M Kirschner ◽  
Hendrik Schlee ◽  
Cornelia Kraus ◽  
Ria Schönauer ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Interaction ◽  
Renal Cyst ◽  
Family Members ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Pathogenic Variants ◽  
Autosomal Dominant Polycystic Kidney

PurposeAutosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either PKD1 or PKD2, is characterised by wide interfamilial and intrafamilial phenotypic variability. This study aimed to determine the molecular basis of marked clinical variability in ADPKD family members and sought to analyse whether alterations of WT1 (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation.MethodsADPKD family members underwent clinical and molecular evaluation. Functionally, Pkd1 mRNA and protein expression upon Wt1 knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells.ResultsBy renal gene panel analysis, we identified two pathogenic variants in an individual with maternal history of ADPKD, however, without cystic kidneys but polycystic liver disease: a known PKD1 missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo WT1 splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/−KTS isoform ratio of WT1. In ex vivo organ cultures from mouse embryonic kidneys, Wt1 knockdown resulted in decreased Pkd1 expression on mRNA and protein level.ConclusionWhile the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with PKD1 proposes WT1 as potential modifier in ADPKD.

scholarly journals Homozygous Missense Mutation on Exon 22 of PKHD1 Gene Causing Fatal Autosomal Recessive Polycystic Kidney Disease

2021 ◽  
Vol 11 (01) ◽  
pp. e70-e73
Author(s):  
Sajina Sathyan ◽  
Femitha Pournami ◽  
Gopala Krishna Madhavilatha ◽  
Amrit Tuteja ◽  
Anand Nandakumar ◽  
...  
Keyword(s):  
Renal Failure ◽  
Respiratory Failure ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Pulmonary Hypoplasia ◽  
Missense Variant ◽  
Diagnostic Techniques ◽  
Polycystic Kidney ◽  
End Stage

AbstractAutosomal recessive polycystic kidney disease, described as a congenital hepatorenal fibrocystic syndrome, is a significant inherited cause of end stage renal failure in children with reported incidence of 1 in 20,000 live births. The clinical spectrum is wide. Antenatal findings of echogenic reniform enlarged kidneys associated with evidence of intrauterine renal failure in the form of severe oligoamnios are pathognomonic. Postnatal illness ranges from fatal respiratory failure due to pulmonary hypoplasia in neonates to chronic kidney disease in children, or later presentation of ductal plate malformation and portal hypertension. Advances in genetic diagnostic techniques have allowed recognition of genotypes. We report a novel homozygous missense variant on exon 22 of PKHD1 gene (chr6:51915067G > A; c.2167C > T) that results in the amino acid substitution of cysteine for arginine at codon 723 (p.Arg723Cys). The affected neonate presented with antenatal anhydramnios, classical radiological features, and severe hypoxic respiratory failure likely due to pulmonary hypoplasia and succumbed. The parents were found to be heterozygous carriers. Detection of the specific variant in the proband facilitated prenatal investigation in the next pregnancy.

Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?

2001 ◽  
Vol 21 (5) ◽  
pp. 430-440 ◽  
Author(s):  
Ira D. Davis ◽  
Katherine MacRae Dell ◽  
William E. Sweeney ◽  
Ellis D. Avner
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Polycystic Kidney

Das polyzystische Syndrom in der deutschen Perserkatzenpopulation

2005 ◽  
Vol 33 (06) ◽  
pp. 413-418 ◽  
Author(s):  
W. Hecht ◽  
M. Gerwing ◽  
U. Michele ◽  
M. Reinacher ◽  
Eva Kappe
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Polycystic Kidney

Zusammenfassung Gegenstand und Ziel: Diese Studie untersuchte das Auftreten einer kürzlich beschriebenen Punktmutation in Form einer C→A-Transversion im Exon 29 des felinen PKD1-Gens in einer Stichprobe der deutschen Perserkatzenpopulation und bei einigen Katzen der Rasse Exotic Shorthair. Diese Mutation führt über ein zusätzliches Stopcodon zum frühzeitigen Abbruch der Proteinkette des Proteins Polycystin. Damit ist sie vermutlicher Auslöser der meisten Fälle des polyzystischen Syndroms (Polycystic Kidney Disease, PKD) bei Perserkatzen. Material und Methoden: Die Untersuchung erfolgte an DNA-Proben von 116 zum Teil miteinander verwandten Perser- und sieben Exotic-Shorthair-Katzen, die im Vorfeld mittels Ultraschall auf die Erkrankung PKD untersucht wurden. Infolge der Punktmutation entsteht eine neue Schnittstellen für das Restriktionsenzym Mly I. Durch eine Restriktionsfragmentanalyse kann das Wildtypallel vom mutierten Allel unterschieden werden. Ergebnisse: Keine der 58 sonographisch zystenfreien Katzen erwies sich als Träger der Mutation. Bei 95% der Perserkatzen mit Nierenzysten und bei allen zystenpositiven Exotic-Shorthair-Tieren war die untersuchte Mutation vorhanden. Damit stimmen die Ergebnisse der Ultraschalluntersuchung und des Gentests zu 97,4% überein. Alle Träger der Mutation waren heterozygot für dieses Merkmal. Schlussfolgerungen: Die Ergebnisse weisen darauf hin, dass es sich bei der untersuchten Mutation um den tatsächlichen Auslöser des polyzystischen Syndroms handelt. Die homozygot vererbte Mutation scheint ein Letalfaktor zu sein, denn homozygote Merkmalsträger wurden nicht beobachtet. Bei 5% der untersuchten Perserkatzen mit Nierenzysten lag keine Mutation in Exon 29 des PKD1-Gens vor. In solchen Fällen kann jedoch eine Mutation an anderer Stelle nicht mit Sicherheit ausgeschlossen werden.

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