Type of PKD1 Mutation Influences Renal Outcome in ADPKD

Gall, Emilie Cornec-Le; Audrézet, Marie-Pierre; Chen, Jian‐Min; Hourmant, Maryvonne; Morin, Marie‐Pascale; Perrichot, Régine; Charasse, Christophe; Whebe, B.; Renaudineau, Éric; Jousset, Philippe; Guillodo, Marie-Paule; Grall-Jezequel, Anne; Saliou, Philippe; Férec, Claude; Meur, Yann Le

doi:10.1681/asn.2012070650

Cited by 417 publications

(314 citation statements)

References 27 publications

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“…This is consistent with results of a recent report showing that the type of PKD1 mutation, but not its protein location, correlated strongly with renal survival of the patients (65). Moreover, our data predict that a subset of PKD1 mutations affecting the CTF sequence would retain both Pc1 cFL and Pc1 deN in the ER without affecting GPS cleavage.…”

Section: Discussionsupporting

confidence: 92%

Novel Functional Complexity of Polycystin-1 by GPS Cleavage In Vivo: Role in Polycystic Kidney Disease

Kurbegovic

Kim

et al. 2014

Molecular and Cellular Biology

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dPolycystin-1 (Pc1) cleavage at the G protein-coupled receptor (GPCR) proteolytic site (GPS) is required for normal kidney morphology in humans and mice. We found a complex pattern of endogenous Pc1 forms by GPS cleavage. GPS cleavage generates not only the heterodimeric cleaved full-length Pc1 (Pc1 cFL ) in which the N-terminal fragment (NTF) remains noncovalently associated with the C-terminal fragment (CTF) but also a novel (Pc1) form (Pc1 deN ) in which NTF becomes detached from CTF. Uncleaved Pc1 (Pc1 U ) resides primarily in the endoplasmic reticulum (ER), whereas both Pc1 cFL and Pc1 deN traffic through the secretory pathway in vivo. GPS cleavage is not a prerequisite, however, for Pc1 trafficking in vivo. Importantly, Pc1 deN is predominantly found at the plasma membrane of renal epithelial cells. By functional genetic complementation with five Pkd1 mouse models, we discovered that CTF plays a crucial role in Pc1 deN trafficking. Our studies support GPS cleavage as a critical regulatory mechanism of Pc1 biogenesis and trafficking for proper kidney development and homeostasis.

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Section: Discussionsupporting

confidence: 92%

Novel Functional Complexity of Polycystin-1 by GPS Cleavage In Vivo: Role in Polycystic Kidney Disease

Kurbegovic

Kim

et al. 2014

Molecular and Cellular Biology

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“…Among the five definitely and highly likely pathogenic variants, 60% (3/5) truncation mutations and 40% (2/5) frameshift mutations found in association with ADPKD in this study are consistent with the findings of previous reports [14,27,37], which further demonstrates that the modified LRNS method can be used to efficiently and specifically make an ADPKD diagnosis.…”

Section: Discussionsupporting

confidence: 91%

Modification of PCR Conditions and Design of Exon-Specific Primers for the Efficient Molecular Diagnosis of PKD1 Mutations

Liu

Chen

Wei

et al. 2014

Kidney Blood Press Res

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Background/Aims: Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by mutations in the PKD1 and PKD2 genes. Currently, long-range PCR followed by nested PCR and sequencing (LRNS) is the gold standard approach for PKD1 testing. However, LRNS is complicated by the high structural and sequence complexity of PKD1, which makes the procedure for amplification and analysis of PKD1 difficult. Methods: Here in, we modified the PCR conditions and designed primers for efficient and specific amplification of both the long-range and individual exons of PKD1. Results: Using the modified system, seven long-range fragments were specifically amplified using two distinct sets of conditions, and all individual exon PCR assays were easily performed using a touch-down PCR method. Seven pathogenic or likely pathogenic variants, including two novel truncated frameshift indels and two novel likely pathogenic missense mutations, were identified in eight unrelated patients with or without histories of ADPKD disease (one variant was observed in two unrelated patients). Using combined bioinformatics tools, two indeterminate missense variants were identified in two sporadic patients. Conclusion: Four novel PKD1 variants were identified in this study. We demonstrated that the modified LRNS method achieves high sensitivity and specificity for detecting pathogenic variants of ADPKD.

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“…Although these correlations are not entirely understood, a recent ADPKD mutation screening study concludes that PKD1 truncating mutations are associated with much early onset of ESRD than nontruncating mutations. 54 Pre-mRNA splicing defects are likely to have an impact on clinical practice as these seem to have a role in practically all known diseases with a genetic origin. 23 An understanding of the role of pre-mRNA splicing in disease increases potential chances to explore therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Splicing defects caused by exonic mutations inPKD1as a new mechanism of pathogenesis in autosomal dominant polycystic kidney disease

2015

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T he correct splicing of precursormRNA depends on the actual splice sites plus exonic and intronic regulatory elements recognized by the splicing machinery. Surprisingly, an increasing number of examples reveal that exonic mutations disrupt the binding of splicing factors to these sequences or generate new splice sites or regulatory elements, causing disease. This contradicts the general assumption that missense mutations disrupt protein function and that synonymous mutations are merely polymorphisms. Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused mainly by mutations in the PKD1 gene. Recently, we analyzed a substantial number of PKD1 missense or synonymous mutations to further characterize their consequences on pre-mRNA splicing. Our results showed that one missense and 2 synonymous mutations induce significant defects in pre-mRNA splicing. Thus, it appears that aberrant splicing as a result of exonic mutations is a previously unrecognized cause of ADPKD.

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Type of PKD1 Mutation Influences Renal Outcome in ADPKD

Cited by 417 publications

References 27 publications

Novel Functional Complexity of Polycystin-1 by GPS Cleavage In Vivo: Role in Polycystic Kidney Disease

Novel Functional Complexity of Polycystin-1 by GPS Cleavage In Vivo: Role in Polycystic Kidney Disease

Modification of PCR Conditions and Design of Exon-Specific Primers for the Efficient Molecular Diagnosis of PKD1 Mutations

Splicing defects caused by exonic mutations inPKD1as a new mechanism of pathogenesis in autosomal dominant polycystic kidney disease

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