DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited renal diseases. ADPKD is a genetically heterogeneous disorder involving at least three different genes. PKD1, the major locus mapped to chromosome 16p13.3 accounts for approximately 85% of ADPKD cases. The search for mutations is a very important step in understanding the molecular mechanisms underlying ADPKD. Despite intense screening by many groups, only a small number of mutations have been described so far. We undertook the first study using denaturing gradient gel electrophoresis (DGGE) to scan for mutations in the non-duplicated region of the PKD1 gene in a large cohort of 146 French unrelated ADPKD patients. We successfully identified novel mutations: 3 are frameshift mutations, 2 nonsense mutations, 2 missense mutations, 1 is an insertion in the frame of 9 nucleotides, 3 intronic variations and several polymorphisms. One of these mutations is the fourth de novo mutation described in this gene. We also describe a family with possible clinical anticipation. DGGE is an effective method for detecting nucleotide changes in the PKD1 gene.

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.…”

Mutation detection for exons 2 to 10 of the Polycystic Kidney Disease 1 (PKD1)-gene by DGGE

“…DGGE-analysis for other parts of the gene have been reported previously. 10,11 All the available data suggest that with a few exceptions 4 each family with ADPKD has its own`private' mutation. The mutation detection rate for the gene as a whole is around 60% …”

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

“…At the present time, only the last 112 C-terminal residues of polycystin-1 have been convincingly shown to be involved in the regulation of a calcium channel, most probably through interaction with polycystin-2. This explains why mutations as far C-terminal as C4086X and others, 19,31,42 which result in removing the crucial polycystin-1 fragment that is implicated in regulating a cation channel, 12 result also in cyst formation and disease development.…”