In the last few years it has become clear that polycystic kidney diseases (PKDs) are ciliopathies, due to mutations in cilia related genes. In this proposal we will study two apparently recessively inherited PKDs, autosomal recessive PKD (ARPKD) and Meckel syndrome (MKS). In ARPKD, the disease is largely restricted to the kidney and liver, while MKS is a lethal, syndromic PKD in which central nervous system and digital defects are typically also found. ARPKD is considered a genetically homogenous disorder due to PKHD1 mutation, although studies of large populations with an ARPKD-like phenotype have found PKHD1 mutations in only about one half of individuals. MKS is genetically more complex with 11 genes identified and alleles at other loci also thought to play a role;possible oligogenic inheritance. Although on the surface these diseases appear very different, recent publications and our preliminary data suggest genetic overlap. Hypomorphic mutations in the autosomal dominant PKD (ADPKD) gene, PKD1, have been shown to cause an ARPKD-like disease and exon enrichment and NGS has shown PKHD1, and the related PKHDL1, alleles in MKS patients. The purpose of this study is to employ cutting-edge genetic methods to understand the full genetic load in these two disorders, while animal models will be utilized to determine the significance of detected variants, plus the strength of epistatic effects between ciliopathy genes. In the first aim a total of ~100 MKS and ~200 ARPKD-like families, that are genetically unresolved, will be analyzed by exon enrichment and next-generation sequencing of ciliopathy and other ciliogenes, plus, when appropriate, whole exome analysis. Variants will be assessed bioinformatically and in Aim 2 cellular systems and the model organisms C. elegans and zebrafish employed to assess the significance of the most promising variants. The concept that the phenotype found in MKS and some ARPKD-like families is due to alleles at more than one gene, that epistasis plays a central role, will be tested in Aim 3 employing C. elegans, zebrafish and interbreeding of mouse models of ciliopathies.
The final aim will explore the role of the PKHD1 paralog and suspected ciliogene, PKHDL1, by developing knock- in/out mouse models to characterize expression and the phenotype associated with disruption of all transcripts. Together these studies will provide a much clearer view of the etiology of ARPKD-like disease and MKS and clarify the true complexity of these """"""""simple"""""""" genetic diseases.

Public Health Relevance

Polycystic kidney diseases (PKD) are a group of inherited disorders that result in cyst development in the kidney resulting in renal failure and a range of morbidities beyond the kidney. In this grant we will study two severe forms of PKD, ARPKD and Meckel syndrome (MKS) that result in utero and neonatal disease, and often result in death. These have been considered recessively inherited disorders but with new genetic tools we are uncovering more genetic complexity. Here we will determine the genetic cause of these disorders, not only in terms of the disease causing mutations but also identifying other genes that may modify the way the disease presents and progresses. Various cellular and model animal systems will be employed to determine the importance of DNA variants identified and genetic interaction between genes. These studies will be of diagnostic and prognostic importance in these disorders and help to understand the true complexity of simple genetic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK059597-11
Application #
8234266
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (04))
Program Officer
Rasooly, Rebekah S
Project Start
2001-04-01
Project End
2017-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
11
Fiscal Year
2012
Total Cost
$311,264
Indirect Cost
$113,887
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Boczek, Nicole J; Hopp, Katharina; Benoit, Lacey et al. (2018) Characterization of three ciliopathy pedigrees expands the phenotype associated with biallelic C2CD3 variants. Eur J Hum Genet 26:1797-1809
Lanktree, Matthew B; Haghighi, Amirreza; Guiard, Elsa et al. (2018) Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J Am Soc Nephrol 29:2593-2600
Yin, Meng; Glaser, Kevin J; Manduca, Armando et al. (2017) Distinguishing between Hepatic Inflammation and Fibrosis with MR Elastography. Radiology 284:694-705
Holditch, Sara J; Schreiber, Claire A; Harris, Peter C et al. (2017) B-type natriuretic peptide overexpression ameliorates hepatorenal fibrocystic disease in a rat model of polycystic kidney disease. Kidney Int 92:657-668
Schueler, Markus; Braun, Daniela A; Chandrasekar, Gayathri et al. (2015) DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. Am J Hum Genet 96:81-92
Sussman, Caroline R; Ward, Christopher J; Leightner, Amanda C et al. (2014) Phosphodiesterase 1A modulates cystogenesis in zebrafish. J Am Soc Nephrol 25:2222-30
Freedman, Benjamin S; Lam, Albert Q; Sundsbak, Jamie L et al. (2013) Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations. J Am Soc Nephrol 24:1571-86
Hoff, Sylvia; Halbritter, Jan; Epting, Daniel et al. (2013) ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet 45:951-6
Wei, Qing; Xu, Qingwen; Zhang, Yuxia et al. (2013) Transition fibre protein FBF1 is required for the ciliary entry of assembled intraflagellar transport complexes. Nat Commun 4:2750
Leightner, Amanda C; Hommerding, Cynthia J; Peng, Ying et al. (2013) The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity. Hum Mol Genet 22:2024-40

Showing the most recent 10 out of 24 publications