Transgenic Overexpression of Anks6 Causes Polycystic Kidney Disease in Rats

Neudecker, Sabine; Walz, Rebecca; Menon, K.M.J.; Maier, Elena; Obermüller, Nicholas; Kränzlin, Bettina; Gretz, Norbert; Hoffmann, Sigrid

doi:10.2353/ajpath.2010.100569

Cited by 29 publications

(19 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the absence of published information regarding ANKS6 expression in the human fetal kidney, we performed immunohistochemistry in first-, second-, and third-trimester kidney tissues. Consistent with published animal data, 21 we found strong staining in S-shaped bodies and the Bowman's capsule but moderate staining in glomeruli of fetuses in the first and second trimesters of pregnancy. As the fetus develops, ANKS6 expression is restricted to the tubular epithelium and disappears from the glomeruli (Figure 2, B-E).…”

supporting

confidence: 92%

“…In addition, in neonatal PKD/Mhm(cy/+) rats, distinct Anks6 (p.R823W) mRNA expression has been found in the tubular epithelium and in podocytes. 21 Glomerular cysts have been reported in homozygous Nek8 knockout mice and in men harboring homozygous truncating NPHP3 mutations. 33,34 Moreover, the homozygous Pro209Leu mutation in TTC21B (encoding the cilia protein IFT139), which has previously been associated with isolated NPHP, was unexpectedly found to cause nephrotic syndrome/FSGS in seven families.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mutations in ANKS6 Cause a Nephronophthisis-Like Phenotype with ESRD

Taşkıran

Korkmaz

Güçer³

et al. 2014

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Nephronophthisis (NPHP) is one of the most common genetic causes of CKD; however, the underlying genetic abnormalities have been established in ,50% of patients. We performed genome-wide analysis followed by targeted resequencing in a Turkish consanguineous multiplex family and identified a canonic splice site mutation in ANKS6 associated with an NPHP-like phenotype. Furthermore, we identified four additional ANKS6 variants in a cohort of 56 unrelated patients diagnosed with CKD due to nephronophthisis, chronic GN, interstitial nephritis, or unknown etiology. Immunohistochemistry in human embryonic kidney tissue demonstrated that the expression patterns of ANKS6 change substantially during development. Furthermore, we detected increased levels of both total and active b-catenin in precystic tubuli in Han:SPRD Cy/+ rats. Overall, these data indicate the importance of ANKS6 in human kidney development and suggest a mechanism by which mutations in ANKS6 may contribute to an NPHP-like phenotype in humans.

show abstract

supporting

confidence: 92%

mentioning

confidence: 99%

Mutations in ANKS6 Cause a Nephronophthisis-Like Phenotype with ESRD

Taşkıran

Korkmaz

Güçer³

et al. 2014

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…4,24 However, in a newborn transgenic rat overexpressing the Anks6 R823W cDNA, cysts predominantly originate from the proximal tubules regardless of the expression of the transgene in other nephron segments including glomerular podocytes. 5 Similarly, ANKS6 is expressed in proximal tubules in control and ANKS6 I747N mice, whereas this nephron segment never develops cysts. Of interest, Pkd1 mouse models also show heterogeneity in the segments affected.…”

Section: Discussionmentioning

confidence: 98%

“…3 The PKD phenotype/genotype analysis of transgenic rats overexpressing Anks6 R823W showed that the R823W point mutation acts in a dominant negative manner. 5 Although the significance of Anks6 in PKD was demonstrated, its biological function and the molecular mechanisms leading to renal cyst formation are still largely unknown.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…thus, the abnormal expression of Samcystin may affect the normal structure and function of the proximal tubules. Neudecker et al developed transgenic rats with Anks6 (p.R823W) , a missense mutation (c>t) of the responsible PKD gene in the cy strain [37]. in this model, the expression of Anks6 is increased either in the immature or mature stages of kidney development, and the cysts are derived from the proximal tubules as in the Cy/+ rats of the spontaneous model, suggesting that gain-of-function by the mutated gene product may cause the disease.…”

Section: Spontaneous Hereditary Models Of Pkdmentioning

confidence: 99%

Animal Models for Human Polycystic Kidney Disease

et al. 2012

View full text Add to dashboard Cite

Polycystic kidney disease (PKD) is a hereditary disorder with abnormal cellular proliferation, fluid accumulation in numerous cysts, remodeling of extracellular matrix, inflammation, and fibrosis in the kidney and liver. The two major types of PKD show autosomal dominant (ADPKD) or autosomal recessive inheritance (ARPKD). ADPKD is one of the most common genetic diseases, with an incidence of 1:500-1,000. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the age of 60. On the other hand, ARPKD is relatively rare, with an incidence of approximately 1:20,000-40,000. ARPKD is diagnosed early in life, often prenatally. The gene products responsible for ADPKD and ARPKD distribute in primary cilia and are thought to control intercellular Ca 2+ . Two types of animal model of PKD have been established: spontaneous hereditary models identified by the typical manifestations of PKD and gene-engineered models established by modification of human orthologous genes. Both types of animal models are used to study the mechanism of cystogenesis and efficacy of medical treatments. In PKD progression, critical roles of signaling pathways including MAPK, mTOR, and PPAR-γ have been discovered with these models. Therefore, experimental animal models are indispensable for investigating molecular mechanisms of PKD onset and progression as well as potential therapeutic treatments.

show abstract

Transgenic Overexpression of Anks6 Causes Polycystic Kidney Disease in Rats

Cited by 29 publications

References 28 publications

Mutations in ANKS6 Cause a Nephronophthisis-Like Phenotype with ESRD

Mutations in ANKS6 Cause a Nephronophthisis-Like Phenotype with ESRD

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

Animal Models for Human Polycystic Kidney Disease

Contact Info

Product

Resources

About