Glomerular and proximal tubule cysts as early manifestations of Pkd1 deletion

Ahrabi, Ali K.; Jouret, François; Marbaix, Étienne; Delporte, Christine; Horie, Shigeo; Mulroy, Sharon; Boulter, Catherine A.; Sandford, Richard; Devuyst, Olivier

doi:10.1093/ndt/gfp611

Cited by 31 publications

(30 citation statements)

References 28 publications

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“…This is consistent with PT cysts predominating in early-onset ADPKD cases, with a similar shift from PT to CD cysts associated with completion of kidney development in ARPKD (28,29,39,76,77). The observation that the majority of adult cysts are of CD origin correlates with the AVPR2 antagonists showing some benefit in ADPKD (31,32,78).…”

Section: Figuresupporting

confidence: 68%

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

et al. 2012

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1 +/null mice are normal, Pkd1 RC/null mice have rapidly progressive disease, and Pkd1 RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/ trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.

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Section: Figuresupporting

confidence: 68%

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

et al. 2012

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“…Of interest, Pkd1 mouse models also show heterogeneity in the segments affected. 25,26 Although ANKS6 rat and mouse mutations are located in the same SAM domain and are physically close, they might induce different conformational changes in the rat and the mouse, which would alter different ANKS6 functions, and/or disrupt interactions with different protein partners. This hypothesis is supported by the replacement of a hydrophilic (arginine) by a hydrophobic (tryptophan) amino acid in cy/+ rat and of a hydrophobic (isoleucine) by a hydrophilic (asparagine) amino acid substitution in ANKS6 I747N mouse.…”

Section: Discussionmentioning

confidence: 99%

The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes

Bakey

Piedagnel

Delestré

et al. 2015

Kidney International

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The ankyrin repeat and sterile α motif (SAM) domain-containing six gene (Anks6) is a candidate for polycystic kidney disease (PKD). Originally identified in the PKD/Mhm(cy/+) rat model of PKD, the disease is caused by a mutation (R823W) in the SAM domain of the encoded protein. Recent studies support the etiological role of the ANKS6 SAM domain in human cystic diseases, but its function in kidney remains unknown. To investigate the role of ANKS6 in cyst formation, we screened an archive of N-ethyl-N-nitrosourea-treated mice and derived a strain carrying a missense mutation (I747N) within the SAM domain of ANKS6. This mutation is only six amino acids away from the PKD-causing mutation (R823W) in cy/+ rats. Evidence of renal cysts in these mice confirmed the crucial role of the SAM domain of ANKS6 in kidney function. Comparative phenotype analysis in cy/+ rats and our Anks6(I747N) mice further showed that the two models display noticeably different PKD phenotypes and that there is a defective interaction between ANKS6 with ANKS3 in the rat and between ANKS6 and BICC1 (bicaudal C homolog 1) in the mouse. Thus, our data demonstrate the importance of ANKS6 for kidney structure integrity and the essential mediating role of its SAM domain in the formation of protein complexes.

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“…PC1 regulates terminal differentiation of tubular structures in kidney and liver (2)(3)(4), as well as maintaining the structural integrity of the kidney (5) and vasculature (6). Expression studies in human and mouse showed spatiotemporal regulated expression for PC1/Pc1 (7)(8)(9)(10).…”

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confidence: 99%

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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Glomerular and proximal tubule cysts as early manifestations of Pkd1 deletion

Cited by 31 publications

References 28 publications

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes

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

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