Screening the 3? region of the polycystic kidney disease 1 (PKD1) gene in 41 Bulgarian and Australian kindreds reveals a prevalence of protein truncating mutations

Abstract

Screening for disease‐causing mutations in the unique region of the polycystic kidney disease 1 (PKD1) gene was performed in 41 unrelated individuals with autosomal dominant polycystic kidney disease. Exons 34‐41 and 43‐46 were assayed using PCR amplification and SSCP analysis followed by direct sequencing of amplicons presenting variant SSCP patterns. We have identified seven disease‐causing mutations of which five are novel [c.10634‐10656del; c.11587delG; IVS37–10C>A; c.11669‐11674del; c.13069‐13070ins39] and two have been reported previously [Q4010X; Q4041X]. Defects in this part of the gene thus account for 17% of our group of patients. Five of the seven sequence alterations detected are protein‐truncating which is in agreement with mutation screening data for this part of the gene by other groups. The two other mutations are in‐frame deletions or insertions which could destroy important functional properties of polycystin 1. These findings suggest that the first step toward cyst formation in PKD1 patients is the loss of one functional copy of polycystin 1, which indirectly supports the “two‐hit” model of cystogenesis where a second somatic mutation inactivating the normal allele is necessary to occur for development of the disease condition. Hum Mutat 16:166–174, 2000. © 2000 Wiley‐Liss, Inc.

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

“…These variants as well as two others were predicted to result in improper splicing by both the ASSA and SSPNN programs (Supp Table 2). In addition, IVS37-10C>A (JHU 604), was previously reported to segregate with ADPKD in a European family [38]. Although these intronic variants are likely to represent splicing mutations, aberrant splicing could not be confirmed at the RNA level using this DNA based assay.…”

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

“…These variants as well as two others were predicted to result in improper splicing by both the ASSA and SSPNN programs (Supp Table 2). In addition, IVS37-10C>A (JHU 604), was previously reported to segregate with ADPKD in a European family [38]. Although these intronic variants are likely to represent splicing mutations, aberrant splicing could not be confirmed at the RNA level using this DNA based assay.…”

Meta‐Analysis of gross insertions causing human genetic disease: Novel mutational mechanisms and the role of replication slippage

“…Interpretation of a 39-bp insertion in the PKD1 gene [Bogdanova et al, 2000], a 29-bp insertion in the ATM gene [Vorechovsky et al, 1996], and a 27-bp insertion in the TCF1 gene [Godart et al, 2000]. Identical nucleotides between the inserted sequences and their wild-type 5 0 £anking sequences are shaded or in bold.…”

Mutations of the PKD1 gene among Japanese autosomal dominant polycystic kidney disease patients, including one heterozygous mutation identified in members of the same family

“…Previous reports suggested that new mutations of the PKD1 gene occur at a significant rate (Peral et al 1997;Rossetti et al 2001). Approximately 80% of the mutations in the 3ЈPKD1 unique region (exons 34-46) were predicted to truncate the protein, and 37% of mutations in the 5Јpart of the gene were missense mutations (Bogdanova et al 2000). More mutations were found in exons 15, 23, 25, and 44, but these exons are not considered hot spots for mutations.…”

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

“…These variants as well as two others were predicted to result in improper splicing by both the ASSA and SSPNN programs (Supp Table 2). In addition, IVS37-10C>A (JHU 604), was previously reported to segregate with ADPKD in a European family [38]. Although these intronic variants are likely to represent splicing mutations, aberrant splicing could not be confirmed at the RNA level using this DNA based assay.…”

Meta‐Analysis of gross insertions causing human genetic disease: Novel mutational mechanisms and the role of replication slippage

“…Interpretation of a 39-bp insertion in the PKD1 gene [Bogdanova et al, 2000], a 29-bp insertion in the ATM gene [Vorechovsky et al, 1996], and a 27-bp insertion in the TCF1 gene [Godart et al, 2000]. Identical nucleotides between the inserted sequences and their wild-type 5 0 £anking sequences are shaded or in bold.…”

Mutations of the PKD1 gene among Japanese autosomal dominant polycystic kidney disease patients, including one heterozygous mutation identified in members of the same family

“…Previous reports suggested that new mutations of the PKD1 gene occur at a significant rate (Peral et al 1997;Rossetti et al 2001). Approximately 80% of the mutations in the 3ЈPKD1 unique region (exons 34-46) were predicted to truncate the protein, and 37% of mutations in the 5Јpart of the gene were missense mutations (Bogdanova et al 2000). More mutations were found in exons 15, 23, 25, and 44, but these exons are not considered hot spots for mutations.…”

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

“…These variants as well as two others were predicted to result in improper splicing by both the ASSA and SSPNN programs (Supp Table 2). In addition, IVS37-10C>A (JHU 604), was previously reported to segregate with ADPKD in a European family [38]. Although these intronic variants are likely to represent splicing mutations, aberrant splicing could not be confirmed at the RNA level using this DNA based assay.…”

Meta‐Analysis of gross insertions causing human genetic disease: Novel mutational mechanisms and the role of replication slippage

“…Interpretation of a 39-bp insertion in the PKD1 gene [Bogdanova et al, 2000], a 29-bp insertion in the ATM gene [Vorechovsky et al, 1996], and a 27-bp insertion in the TCF1 gene [Godart et al, 2000]. Identical nucleotides between the inserted sequences and their wild-type 5 0 £anking sequences are shaded or in bold.…”

Mutations of the PKD1 gene among Japanese autosomal dominant polycystic kidney disease patients, including one heterozygous mutation identified in members of the same family

“…Previous reports suggested that new mutations of the PKD1 gene occur at a significant rate (Peral et al 1997;Rossetti et al 2001). Approximately 80% of the mutations in the 3ЈPKD1 unique region (exons 34-46) were predicted to truncate the protein, and 37% of mutations in the 5Јpart of the gene were missense mutations (Bogdanova et al 2000). More mutations were found in exons 15, 23, 25, and 44, but these exons are not considered hot spots for mutations.…”