Abstract
BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The disease is caused by mutations of the PKD1 (affecting roughly 85% of ADPKD patients) and PKD2 (affecting roughly 14% of ADPKD patients) genes, although in several ADPKD families, the PKD1 and/or PKD2 linkage was not found. Mutation analysis of the PKD1 gene is complicated by the presence of highly homologous genomic duplications of the first two thirds of the gene.MethodsThe direct detection of mutations in the non-duplicated region of the PKD1 gene was performed in 90 unrelated individuals, consisting of 58 patients with end-stage renal failure (manifesting before their 50th year of life) and 32 individuals from families where the disease was clearly linked to the PKD1 gene. Mutation screening was performed using denaturing gradient gel electrophoresis (DGGE). DNA fragments showing an aberrant electrophoretic banding pattern were sequenced.ResultsIn the non-duplicated region of the PKD1 gene, 19 different likely pathogenic germline sequence changes were identified in 19 unrelated families/individuals. Fifteen likely pathogenic sequence changes are unique for the Czech population. The following probable mutations were identified: 9 nonsense mutations, 6 likely pathogenic missense mutations, 2 frameshifting mutations, one in-frame deletion and probable splice site mutation. In the non-duplicated region of the PKD1 gene, 16 different polymorphisms or unclassified variants were detected.ConclusionTwenty probable mutations of the PKD1 gene in 90 Czech individuals (fifteen new probable mutations) were detected. The establishment of localization and the type of causal mutations and their genotype - phenotype correlation in ADPKD families will improve DNA diagnosis and could help in the assessment of the clinical prognosis of ADPKD patients.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease
The PKD1 locus (MIM 601313) is linked to the short arm of chromosome 16, at 16p13.3 [3,4]; and so far, 818 different sequence variants have been reported in Polycystic Kidney Disease Mutation Database (PKDB) [5]
Eightyfive percent of ADPKD cases are caused by a mutation of the PKD1 gene on chromosome 16 and in about 15% of all cases, the PKD2 gene on chromosome 4 is mutated [8]
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The disease is caused by mutations of the PKD1 (affecting roughly 85% of ADPKD patients) and PKD2 (affecting roughly 14% of ADPKD patients) genes, in several ADPKD families, the PKD1 and/or PKD2 linkage was not found. The PKD1 locus (MIM 601313) is linked to the short arm of chromosome 16, at 16p13.3 [3,4]; and so far, 818 different sequence variants have been reported in Polycystic Kidney Disease Mutation Database (PKDB) [5]. A second locus PKD2 (MIM 173910) was located on chromosome 4q21 [6]; and 123 different sequence variants have been reported in PKDB [5]. The average age of PKD1 patients at end-stage renal disease (ESRD) is 54.3 years compared with 74.0 years for PKD2 patients [9]
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