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

Bogdanova, Nadja; McCluskey, Marie; K, Sikmann; Markoff, Arseni; Todorov, Vassil; Dimitrakov, D; Schiavello, T; Thomas, Mark; Kalaydjieva, Luba; Dworniczak, Bernd; Horst, Jürgen

doi:10.1002/1098-1004(200008)16:2<166::aid-humu9>3.0.co;2-4

Cited by 8 publications

(3 citation statements)

References 38 publications

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“…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.…”

Section: Class II Testsmentioning

confidence: 87%

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

García-González

Jones²,

Allen³

et al. 2007

Molecular Genetics and Metabolism

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Autosomal dominant polycystic kidney disease (ADPKD) is estimated to affect 1/600-1/1000 individuals worldwide. The disease is characterized by age dependent renal cyst formation that results in kidney failure during adulthood. Although ultrasound imaging may be an adequate diagnostic tool in at risk individuals older than 30, this modality may not be sufficiently sensitive in younger individuals or for those from PKD2 families who have milder disease. DNA based assays may be indicated in certain clinical situations where imaging cannot provide a definitive clinical diagnosis. The goal of this study was to evaluate the utility of direct DNA analysis in a test sample of 82 individuals who were judged to have polycystic kidney disease by standard clinical criteria. The samples were analyzed using a commercially available assay that employs sequencing of both genes responsible for the disorder. Definite disease causing mutations were identified in 34 (approximately 42%) study participants. An additional 30 (approximately 37%) subjects had either in frame insertions/deletions, non-canonical splice site alterations or a combination of missense changes that were also judged likely to be pathogenic. We noted striking sequence variability in the PKD1 gene, with a mean of 13.1 variants per participant (range 0-60). Our results and analysis highlight the complexity of assessing the pathogenicity of missense variants particularly when individuals have multiple amino acid substitutions. We conclude that a significant fraction of ADPKD mutations are caused by amino acid substitutions that need to be interpreted carefully when utilized in clinical decision-making.

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Section: Class II Testsmentioning

confidence: 87%

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

García-González

Jones²,

Allen³

et al. 2007

Molecular Genetics and Metabolism

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“…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.…”

Section: Normal Replicationmentioning

confidence: 99%

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

et al. 2005

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Although gross insertions (>20 bp) comprise <1% of disease-causing mutations, they nevertheless represent an important category of pathological lesion. In an attempt to study these insertions in a systematic way, 158 gross insertions ranging in size between 21 bp and approximately 10 kb were identified using the Human Gene Mutation Database (www.hgmd.org). A careful meta-analytical study revealed extensive diversity in terms of the nature of the inserted DNA sequence and has provided new insights into the underlying mutational mechanisms. Some 70% of gross insertions were found to represent sequence duplications of different types (tandem, partial tandem, or complex). Although most of the tandem duplications were explicable by simple replication slippage, the three complex duplications appear to result from multiple slippage events. Some 11% of gross insertions were attributable to nonpolyglutamine repeat expansions (including octapeptide repeat expansions in the prion protein gene [PRNP] and polyalanine tract expansions) and evidence is presented to support the contention that these mutations are also caused by replication slippage rather than by unequal crossing over. Some 17% of gross insertions, all >or=276 bp in length, were found to be due to LINE-1 (L1) retrotransposition involving different types of element (L1 trans-driven Alu, L1 direct, and L1 trans-driven SVA). A second example of pathological mitochondrial-nuclear sequence transfer was identified in the USH1C gene but appears to arise via a novel mechanism, trans-replication slippage. Finally, evidence for another novel mechanism of human genetic disease, involving the possible capture of DNA oligonucleotides, is presented in the context of a 26-bp insertion into the ERCC6 gene.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Mizoguchi¹,

Tamura²,

Yamaki³

et al. 2001

J Hum Genet

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More than 80 mutations of the PKD1 gene have been reported, mostly in patients from Western Europe. New techniques are being used to detect an increasing number of mutations, even in the homologous region of the PKD1 gene. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) or denaturing highperformance liquid chromatography (DHPLC) analyses were performed in the present study to screen mutations from exon 23 to exon 46 in the PKD1 gene and in the entire PKD2 gene. When an abnormal pattern was found in PCR-SSCP or DHPLC, the PCR products were directly sequenced. Four mutations were identified in the PKD1 gene: a missense mutation (C47413T causing T3509M in exon 35), a splicing mutation (del 20 bp in 75 bp of intron 43), and two nonsense mutations (C48566A causing C3693X in exon 38, and C51237T causing Q4124X in exon 45). The nonsense mutation Q4124X existed in only two of three affected sib members in family K68. The pattern of the restriction enzyme digest and the haplotype analysis confirmed the presence of a heterozygous mutation in the family. Fifteen single nucleotide polymorphisms were identified in this study. Two of them (C50439A and C51659T) can be used as intragenic polymorphic markers.

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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

Cited by 8 publications

References 38 publications

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

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

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

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

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