Novel mutations of PKD genes in the Czech population with autosomal dominant polycystic kidney disease

Abstract

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder caused by mutation in either one of two genes, PKD1 and PKD2. High structural and sequence complexity of PKD genes makes the mutational diagnostics of ADPKD challenging. The present study is the first detailed analysis of both PKD genes in a cohort of Czech patients with ADPKD using High Resolution Melting analysis (HRM) and Multiplex Ligation-dependent Probe Amplification (MLPA).MethodsThe mutational analysis of PKD genes was performed in a set of 56 unrelated patients. For mutational screening of the PKD1 gene, the long-range PCR (LR-PCR) strategy followed by nested PCR was used. Resulting PCR fragments were analyzed by HRM; the positive cases were reanalyzed and confirmed by direct sequencing. Negative samples were further examined for sequence changes in the PKD2 gene by the method of HRM and for large rearrangements of both PKD1 and PKD2 genes by MLPA.ResultsScreening of the PKD1 gene revealed 36 different likely pathogenic germline sequence changes in 37 unrelated families/individuals. Twenty-five of these sequence changes were described for the first time. Moreover, a novel large deletion was found within the PKD1 gene in one patient. Via the mutational analysis of the PKD2 gene, two additional likely pathogenic mutations were detected.ConclusionsProbable pathogenic mutation was detected in 71% of screened patients. Determination of PKD mutations and their type and localization within corresponding genes could help to assess clinical prognosis of ADPKD patients and has major benefit for prenatal and/or presymptomatic or preimplantational diagnostics in affected families as well.

Novel Mutations in the PKD1 and PKD2 Genes of Chinese Patients with Autosomal Dominant Polycystic Kidney Disease

“…Consistently, we found that PKD1 mutation carriers had an earlier age of onset of ESRD than those with PKD2 mutations. Moreover, patients with truncating mutations were found to have a more severe clinical outcome than those with non-truncating mutations, which confirmed the strong correlation between mutation type and median age at ESRD onset identified in previous studies [34, 38]. …”

“…Although the pathogenicity of most of the missense mutations evaluated by the prediction tools used in this study was consistent with the results of pedigree analysis, 2 mutations ( PKD1 c.4984G>A and PKD1 c.7544G>C), which were demonstrated as benign mutations by the prediction tools, were identified as pathogenic mutations through pedigree analysis. A similar phenomenon was also found in several other related studies [33, 34]. Due to the nature of ADPKD as a single-gene inherited disease, segregation analysis is recommended as a gold standard to evaluate the pathogenicity of missense mutations rather than prediction tools.…”

Vascular endothelial growth factor as an angiogenesis biomarker for the progression of autosomal dominant polycystic kidney disease

“…Its prevalence, as determined by previous studies, is between 1/400 and 1/1000 live births in the population (Obeidova et al, 2014;Noël and Rieu, 2015). An estimated 600,000 individuals are affected by this disease (Fedeles et al, 2014).…”

“…The identification of SNPs is a new means to study the etiology of polygenetic disorders with complex inheritance patterns (Gurocak et al, 2015). ADPKD may progress to a stage where there is a need for hemodialysis and/or kidney transplant, and is influenced by modifier genes (Obeidova et al, 2014). VEGF, which is responsible for the survival, migration, proliferation, permeability, and dilation of blood vessels, may play an important role in the expansion of renal vasculature and cysts (Huang et al, 2013).…”

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian (Madurai) Population

“…This work, which coincides with the work done by Constantinides [70] among Caucasian and Japanese population, also has revealed the association of C/T4058 polymorphism with ADPKD. The PKD1 gene is responsible for causing autosomal dominant polycystic kidney disease and it has been recently cloned and sequenced [75]. ADPKD is reported to be a very frequent disorder among Caucasian population with an estimated incidence of approximately 1:100.…”