Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families

Abstract

The autosomal dominant form of polycystic kidney disease is a very frequent genetically heterogeneous inherited condition affecting approximately 1 : 1000 individuals of the Caucasian population. The main symptom is the formation of fluid-filled cysts in the kidneys, which grow progressively in size and number with age, and leading to end-stage renal failure in approximately 50% of patients by age 60. About 85% of cases are caused by mutations in the PKD1 gene on chromosome 16p13.3, which encodes for polycystin-1, a membranous glycoprotein with 4302 amino acids and multiple domains. Mutation detection is still a challenge owing to various sequence characteristics that prevent easy PCR amplification and sequencing. Here we attempted a systematic screening of part of the duplicated region of the gene in a large cohort of 53 Hellenic families with the use of single-strand conformation polymorphism analysis of exons 16 ± 34. Our analysis revealed eight most probably disease causing mutations, five deletions and three single amino acid substitutions, in the REJ domain of the protein. In one family, a 3-bp and an 8-bp deletion in exons 20 and 21 respectively, were co-inherited on the same PKD1 chromosome, causing disease in the mother and three sons. Interestingly we did not find any termination codon defects, so common in the unique part of the PKD1 gene. In the same cohort we identified 11 polymorphic sequence variants, four of which resulted in amino acid variations. This supports the notion that the PKD1 gene may be prone to mutagenesis, justifying the relatively high prevalence of polycystic kidney disease.

Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease

“…Five participants, JHU602 (N=2), JHU100 (N=3), JHU588 (N=2), JHU411 (N=2) and JHU114 (N=2), had more than one PKD1 amino acid variant that met the criteria for pathogenicity (Supp Table 4). These observations raise the possibility that a combination of missense changes in cis might cooperatively result in a diminished level of functional protein [41].…”

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

“…They are shown in Supplemental Table 2, with the scores established to evaluate their putative pathogenicity by different programs (see Methods). Six were previously reported, 10,[12][13][14][15] and three were present in our in-house database: p.Thr2710N and p.Arg3183Gln were associated with another PKD1 or PKD2 mutation in patients diagnosed in the fourth decade, and the p.R3277C mutation was identified at the homozygous state in a woman transplanted at 50 years. No additional PKD1 or PKD2 variations were identified in the other patients.…”

Co‐inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease

“…To exclude the possibility that the missense PKD2 variant on both of her alleles is a polymorphism, we screened 280 chromosomes from Greek healthy subjects originating from different areas of Greece and the mutated PKD2 allele was found in none of them. Reported molecular analyses on Greek PKD patients are limited [32,33]. All of the studies revealed mutations in the PKD1 gene [34]; another reported a de‐novo variant located in the REJ module in the long extracellular domain that was similar to our PKD1 variant.…”