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      A New PKD1 Mutation Discovered in a Chinese Family with Autosomal Polycystic Kidney Disease

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          Background/Aims: Autosomal-dominant polycystic kidney disease (ADPKD), a heterogeneous genetic disorder characterized by massive kidney enlargement and progressive chronic kidney disease, is due to abnormal proliferation of renal tubular epithelium. ADPKD is known to be caused by mutations in PKD1 and PKD2 genes. Methods: In the present study, the mutation analysis of PKD genes was performed in a new Chinese family with ADPKD using Long-Range (LR) PCR sequencing and targeted next-generation sequencing (targeted DNA-HiSeq). Results: A unique 28 bp deletion (c.12605_12632del28) in exon 46 of the PKD1 gene was identified in two affected family members by LR PCR method, but not in any unaffected relatives or unrelated controls. Higher accuracy and less missing detection presented in LR PCR method compared with targeted DNA-HiSeq. This mutation c.12605_12632del28 (p.Arg4202ProextX146) resulted in a delayed termination of amino acid code, and was highly speculated pathogenic in this ADPKD family. Moreover, this newly identified frame-shift change was compared to the PKD gene database, but no similar mutation was yet reported. Conclusion: A novel frame-shift mutation, c. 12605_12632del28, in the PKD1 gene was found in a Chinese ADPKD family. All evidence available suggested that it might be the mutation responsible for the disease in that family.

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          Autosomal dominant polycystic kidney disease.

          Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal, monogenic disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of the disorder's underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
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            Type of PKD1 mutation influences renal outcome in ADPKD.

            Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.
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              Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

              Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                July 2014
                30 April 2014
                : 39
                : 1
                : 1-8
                aDepartment of Urology; bDepartment of Emergency; cDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China, dBoth authors contributed equally to this work
                Author notes
                *Jing Xiong, M.D, Ph.D., Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430022 (China), Tel. (86) 85726713, E-Mail: jingandshuyue@gmail.com
                355772 Kidney Blood Press Res 2014;39:1-8
                © 2014 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) ( http://www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Pages: 8
                Original Paper


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