Publications
Stokman MF, Renkema KY, Giles RH, Schaefer F, Knoers NV, van Eerde AM. The expanding phenotypic spectra of kidney disease: insights from genetic studies. Nat Rev Nephrol. 2016 Aug; 12(8):472-83.
In this review in Nature Reviews Nephrology, we describe how new genetic techniques, like whole-exome sequencing, have led to a shift in the classification of kidney diseases. By investigating many genes simultaneously, we find changes in unexpected genes and we see that changes in the same gene can cause a diverse range of kidney diseases. These genetic findings lead to a better understanding of the pathophysiological mechanisms behind kidney diseases, and ultimately to new therapeutic targets. Ciliopathies, which we study within the KOUNCIL consortium, provide excellent examples of the various phenotypes (for example nephronophthisis, Joubert syndrome and Bardet-Biedl syndrome) that can be caused by changes in the same gene.
Stokman M, Lilien M, Knoers N. Nephronophthisis. GeneReviews. 2016 Jun 23; published online: www.ncbi.nlm.nih.gov/books/NBK368475/.
In this GeneReview, we have summarized the most important clinical characteristics and (genetic) diagnostic criteria for nephronophthisis, and we provide information about genetic counseling, surveillance and treatment. This GeneReview is based on the most recent studies on nephronophthisis and can be used by doctors and others who are interested in knowing more about nephronophthisis. We will update this GeneReview every few years with the latest findings from nephronophthisis research.
Boldt K, van Reeuwijk J, Lu Q, Koutroumpas K, Nguyen TM, Texier Y, van Beersum SE, Horn N, Willer JR, Mans DA, Dougherty G, Lamers IJ, Coene KL, Arts HH, Betts MJ, Beyer T, Bolat E, Gloeckner CJ, Haidari K, Hetterschijt L, Iaconis D, Jenkins D, Klose F, Knapp B, Latour B, Letteboer SJ, Marcelis CL, Mitic D, Morleo M, Oud MM, Riemersma M, Rix S, Terhal PA, Toedt G, van Dam TJ, de Vrieze E, Wissinger Y, Wu KM, Apic G, Beales PL, Blacque OE, Gibson TJ, Huynen MA, Katsanis N, Kremer H, Omran H, van Wijk E, Wolfrum U, Kepes F, Davis EE, Franco B, Giles RH, Ueffing M, Russell RB, Roepman R; UK10K Rare Diseases Group. An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nat Commun. 2016 May 13;7:11491.
As part of an international team of researchers, KOUNCIL scientists have systematically identified and mapped new protein components related to cilia (dys)function. Improper cilia development due to genetic defects can result in a range of hereditary disorders called ciliopathies, with common complications such as kidney failure, hearing loss, blindness, skeletal abnormalities, and even cancer, occurring often in combinations. The results in this studygives detailed insights into the connections made by over 1300 proteins as part of ciliary protein complexes, networks or signaling pathways. These insights help to discover new genetic causes for ciliopathies and are important for understanding the disease mechanism of ciliopathies, which is essential knowledge for translational research towards therapies.
Nielsen SM, Rhodes L, Blanco I, Chung WK, Eng C, Maher ER, Richard S, Giles RH. Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome. J Clin Oncol. 2016 Jun 20;34(18):2172-81.
Von Hippel-Lindau (VHL) disease causes patients to have cysts and tumors in their kidneys, brain, spinal cord, pancreas, and adrenal glands, among other sites. VHL is considered an "atypical" ciliopathy, because normally ciliopathy patients do not have a higher risk for tumors. In this paper, we discuss the important role genetic counseling plays in helping these patients manage their complex disease. We discuss the evidence that can help doctors and patients achieve the best-quality care.
Lambacher NJ, Bruel AL, van Dam TJ, Szymańska K, Slaats GG, Kuhns S, McManus GJ, Kennedy JE, Gaff K, Wu KM, van der Lee R, Burglen L, Doummar D, Rivière JB, Faivre L, Attié-Bitach T, Saunier S, Curd A, Peckham M, Giles RH, Johnson CA, Huynen MA, Thauvin-Robinet C, Blacque OE. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nat Cell Biol. 2016 Jan;18(1):122-31.
In this high-impact paper we identify a new protein (TMEM107) at the base of the cilium, and show that mutations in this gene cause Joubert syndrome. Using genetically modified worms, we show that TMEM107 is important to bring other proteins to the cilium and that the cilium is less stable when it cannot perform this function.
Slaats GG, Isabella CR, Kroes HY, Dempsey JC, Gremmels H, Monroe GR, Phelps IG, Duran KJ, Adkins J, Kumar SA, Knutzen DM, Knoers NV, Mendelsohn NJ, Neubauer D, Mastroyianni SD, Vogt J, Worgan L, Karp N, Bowdin S, Glass IA, Parisi MA, Otto EA, Johnson CA, Hildebrandt F, van Haaften G, Giles RH, Doherty D. MKS1 regulates ciliary INPP5E levels in Joubert syndrome. J Med Genet. 2016 Jan;53(1):62-72.
We describe several new mutations in the MKS1 gene we found in Joubert patients. The mutations in MKS1 which cause the more severe Meckel Gruber syndrome are "more severe" than the mutations in the Joubert patients we describe. Using cells from a series of patients – and in some cases their healthy parents- we show that the biggest difference we see in all cases is the placement of a protein called INPP5E (also mutated in some Joubert patients) in the cilium. This paper suggests that the common problem in Joubert patients may be getting INPP5E to the right place, which could also help scientist focus on a way to fix that.
Slaats GG, Wheway G, Foletto V, Szymanska K, van Balkom BW, Logister I, Den Ouden K, Keijzer-Veen MG, Lilien MR, Knoers NV, Johnson CA, Giles RH. Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis. J Cell Sci. 2015 Dec 15;128(24):4550-9.
In the kidney, ion channels are like doors in the cell that let certain salts into or out of the cell. In this paper we found four ion channels that kidney cells need to make cilia. We don't know exactly how these ion channels affect cilia, but we do know that for at least one of them -KCNQ1- mutations in patients with heart rhythm problems actually changes the kidney cilia. Our data suggest that it might be a good idea to check the kidney function of patients with KCNQ1 mutations.
Slaats GG, Saldivar JC, Bacal J, Zeman MK, Kile AC, Hynes AM, Srivastava S, Nazmutdinova J, den Ouden K, Zagers MS, Foletto V, Verhaar MC, Miles C, Sayer JA, Cimprich KA, Giles RH. DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome. J Clin Invest. 2015 Sep;125(9):3657-66.
This is an important paper that shows that the problem in kidney cells from mice and humans with no functional CEP290 (NPHP6) might not start in the cilium, but somewhere else in the cell: at the DNA. Many groups are starting to build evidence that mutations in ciliopathy genes (like CEP290, but there is other evidence for NEK8/NPHP9, SDCCAG8/NPHP10, and CEP164/NPHP14) cause breaks in the DNA when the cells try and divide, and this might be part of the process of cell death and scarring in the kidney. This paper also shows that using drugs like roscovitine, a so-called "CDK inhibitor" which helps cells survive the DNA breaks caused when ciliopathy proteins like CEP290 are mutated, could be an approach to consider minimising the damage in nephronophthisis patients.
Wheway G, Schmidts M, Mans DA, Szymanska K, Nguyen TM, Racher H, Phelps IG, Toedt G, Kennedy J, Wunderlich KA, Sorusch N, Abdelhamed ZA, Natarajan S, Herridge W, van Reeuwijk J, Horn N, Boldt K, Parry DA, Letteboer SJ, Roosing S, Adams M, Bell SM, Bond J, Higgins J, Morrison EE, Tomlinson DC, Slaats GG, van Dam TJ, Huang L, Kessler K, Giessl A, Logan CV, Boyle EA, Shendure J, Anazi S, Aldahmesh M, Al Hazzaa S, Hegele RA, Ober C, Frosk P, Mhanni AA, Chodirker BN, Chudley AE, Lamont R, Bernier FP, Beaulieu CL, Gordon P, Pon RT, Donahue C, Barkovich AJ, Wolf L, Toomes C, Thiel CT, Boycott KM, McKibbin M, Inglehearn CF; UK10K Consortium; University of Washington Center for Mendelian Genomics, Stewart F, Omran H, Huynen MA, Sergouniotis PI, Alkuraya FS, Parboosingh JS, Innes AM, Willoughby CE, Giles RH, Webster AR, Ueffing M, Blacque O, Gleeson JG, Wolfrum U, Beales PL, Gibson T, Doherty D, Mitchison HM, Roepman R, Johnson CA. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat Cell Biol. 2015 Aug;17(8):1074-87.
In this paper we worked with many researchers to systematically shut down every gene one by one, to find out which ones cause problems in making a cilia in mouse kidney cells. This made a large list of both known and unknown genes. The new genes might be good genes to look at in ciliopathy families without a clear diagnosis yet.
Slaats GG, Lilien MR, Giles RH. Nephronophthisis: should we target cysts or fibrosis? Pediatr Neprhol. 2015 July. [Epub ahead of print].
This article published in Pedriatric Nephrology provides an overview of the compounds that have been tested in animal models to ameliorate kidney cysts and fibrosis in nephronophthisis. Researchers explore the mechanisms underlying nephronophthisis that can be targeted with drugs. Should treatment be aimed at reducing cyst formation, should we target molecules involved in fibrosis or both? Contrary to kidney cysts, fibrosis is a feature in all nephronophthisis patients and may be central to decline of renal function. Finally, the authors discuss the mechanism and potential benefits of paclitaxel as a drug to target fibrosis in nephronophthisis and related ciliopathies.
Ajzenberg H, Slaats GG, Stokman MF, Arts HH, Logister I, Kroes HY, Renkema KY, van Haelst MM, Terhal PA, van Rooij IA, Keijzer-Veen MG, Knoers NV, Lilien MR, Jewett MA, Giles RH. Non-invasive sources of cells with primary cilia from pediatric and adult patients. Cilia. 2015 Jun 1;4:8.
In this article published in Cilia, KOUNCIL researchers describe non-invasive methods of obtaining patient cells for research or diagnostics. Urine-derived renal epithelial cells (URECS) and cells isolated from deciduous teeth offer a child-friendly alternative to cells isolated from a skin biopsy. Both urine- and tooth-derived cells can be used to study DNA changes, the effect of patient mutations on cilia structure and the effects of candidate drugs. In addition, URECS can be grown in 3D culture to develop spheroid models of the renal epithelium.
Slaats GG, Giles RH. Are renal ciliopathies (replication) stressed out? Trends Cell Biol. 2015 Jun;25(6):317-9.
This article investigates the mechanism behind nephronophthisis. We know that the proteins involved in nephronophthisis (nephrocystins) localize to the cilia, and that patient-derived cells often have fewer cilia than cells from healthy control subjects. Is the loss of cilia the cause of renal damage or are both the loss of cilia and renal damage the result of replication stress? There is increasing evidence of a dual role of cilia proteins in regulation of cell division and DNA damage response. These mechanisms may underlie renal fibrosis, a hallmark feature of nephronophthisis.
Kroes HY, Monroe GR, van der Zwaag B, Duran KJ, de Kovel CG, van Roosmalen MJ, Harakalova M, Nijman IJ, Kloosterman WP, Giles RH, Knoers NV, van Haaften G. Joubert syndrome: genotyping a Northern European patient cohort. Eur J Hum Genet. 2015 Apr 29. doi: 10.1038/ejhg.2015.84.
This article describes a Northern-European cohort of 51 patients with Joubert syndrome. Testing of 22 known Joubert genes and 599 cilia-related candidate genes resulted in a molecular confirmation of the diagnosis in 21 patients (41%). Six out of 21 patients with a molecular diagnosis had renal problems (29%). Mutations were most prevalent in the genes C5orf42 (12%), TMEM67 (10%) and AHI1 (8%). Patients with mutations in C5orf42 displayed only neurological symptoms. Finally, the authors describe a patient with heterozygous mutations in two genes, CC2D2A and the Meckel-Gruber-associated gene B9D1. Because CC2D2A and B9D1 are both part of the B9-protein complex at the base of the cilium, the combination of heterozygous mutations in these genes may explain the disease in this patient (digenic inheritance).
Schueler et al. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. Am J Hum Genet. 2014; in press.
In KOUNCIL-funded research one of our goals is to identify new genes causing nephronophthisis (NPHP), which will help families find appropriate diagnosis and counselling. In a paper coming out soon in the American Journal of Human Genetics, KOUNCIL members helped find a new gene called
DCDC2 as causing a particular form of NPHP in two families; the liver of all patients with DCDC2 mutations was severely affected as well. Other aspects of ciliopathies (blindness, bone abnormalities, hearing problems, obesity) were not present in these patients, so we conclude that DCDC2 causes a “renal-hepatic-ciliopathy” (ciliopathy of the kidney and liver). Cell biology experiments show that the DCDC2 protein normally helps cilia work and that zebrafish without DCDC2 get NPHP. "Mild” mutations in this gene have been previously associated with reading disabilities/developmental dyslexia. This link will be explored further.
Mans DA, Arts HH. Medical genetics of ciliopathies. J Pediatr Genet. 2014 Nov;3(2):47-48.
KOUNCIL members have been guest-editor and author respectively of a special edition of the Journal of Pediatric Genetics on ciliary disorders. The aim of this issue is to inform pediatricians, scientists and others who are interested about the diagnosis and treatment of ciliary disorders now and in the future. Nephronophthisis and ARPKD are discussed among other diseases. KOUNCIL members have written the chapters on ciliary chondrodysplasias and cancer.
Oud MM, van Bon BW, Bongers EM, Hoischen A, Marcelis CL, de Leeuw N, et al. Early presentation of cystic kidneys in a family with a homozygous INVS mutation. Am J Med Genet A. 2014 Jul; 164A(7):1627-34.
In this paper that was published in the American Journal of Medical Genetics Part A, KOUNCIL members describe the phenotype of a family with nephronophthisis resulting from INVS mutations. It was known previously that INVS mutations lead to infantile nephronophthisis, however the phenotype seen in this family was very severe and unexpectedly included skeletal anomalies. These findings therefore expand the phenotypic spectrum associated with INVS mutations. In addition, the functional effects of the specific INVS mutation are investigated in patient cells.
Renkema KY et al. Next-generation sequencing for research and diagnostics in kidney disease. Nat Rev Nephrol. 2014 June; 10: 433-44.
In this review article we discuss the methods that are used for genetic research and diagnostics of hereditary kidney diseases. We focus on nephronophthisis and congenital anomalies of the kidney and urinary tract (CAKUT). Questions that are addressed are: What are the implications of recent technical developments in the field of DNA investigation for research of hereditary kidney disease? How do we discover new genes and how do we find evidence for the involvement of a genetic defect in the development of the kidney disease? Finally, we discuss the challenges and ethical considerations association with studies like the KOUNCIL study.
Arts HH, Knoers NVAM. Reikwijdte en betekenis van ciliopathieën in de pediatrische praktijk. Tijdschrift voor kindergeneeskunde. 2014, 82(1):19-25.
In this review, the most renal ciliopathies that pediatricians most frequently encounter are discussed in Dutch. The review contains a brief description of cilia and their function. In addition, diagnostics, prognostics and clinical management of isolated and syndromal nephronophthisis are described.
