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Year: 2009

EUNEFRON, the European Network for the Study of OrphanNephropathies

Devuyst, O; Meij, I; Jeunemaitre, X; Ronco, P; Antignac, C; Christensen, E I; Knoers,N V; Levtchenko, E N; Deen, P M; Müller, D; Wagner, C A; Rampoldi, L; Van't Hoff,

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Devuyst, O; Meij, I; Jeunemaitre, X; Ronco, P; Antignac, C; Christensen, E I; Knoers, N V; Levtchenko, E N;Deen, P M; Müller, D; Wagner, C A; Rampoldi, L; Van't Hoff, W G (2009). EUNEFRON, the European Networkfor the Study of Orphan Nephropathies. Nephrology Dialysis Transplantation, Epub ahead of print:1-5.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Nephrology Dialysis Transplantation 2009, Epub ahead of print:1-5.

Devuyst, O; Meij, I; Jeunemaitre, X; Ronco, P; Antignac, C; Christensen, E I; Knoers, N V; Levtchenko, E N;Deen, P M; Müller, D; Wagner, C A; Rampoldi, L; Van't Hoff, W G (2009). EUNEFRON, the European Networkfor the Study of Orphan Nephropathies. Nephrology Dialysis Transplantation, Epub ahead of print:1-5.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Nephrology Dialysis Transplantation 2009, Epub ahead of print:1-5.

Nephrol Dial Transplant (2009) 1 of 5doi: 10.1093/ndt/gfp095

Editorial Comment

EUNEFRON, the European Network for the Study of OrphanNephropathies

Olivier Devuyst1, Iwan Meij2, Xavier Jeunemaitre3, Pierre Ronco3, Corinne Antignac3,Erik I. Christensen4, Nina V. Knoers5, Elena N. Levtchenko5, Peter M. Deen5, Dominik Muller2,Carsten A. Wagner6, Luca Rampoldi7 and William G. van’t Hoff 8 On behalf of the EUNEFRONconsortium

1UCL, Brussels, Belgium, 2Charite MDC, Berlin, Germany, 3INSERM, Paris, France, 4Univ. Aaarhus, Aaarhus, Denmark,5RUNMC, Nijmegen, The Netherlands, 6Inst. Physiology, Univ. Zurich, Zurich, Switzerland, 7Dulbecco Telethon Inst., HSR, Milan,Italy and 8GOSH, London, UK

Correspondence and offprint requests to: Olivier Devuyst; E-mail: olivier.devuyst@uclouvain.be

Keywords: European consortium; genetic disorders; kidney disease;rare diseases

Introduction

There are at least 60 rare inherited diseases affecting thekidney, which, although individually affecting less than oneperson in every 2000, have a large negative impact on thequality of life of the patients, often children, and their fam-ilies [1,2]. The care of patients with rare nephropathiesis hampered by major problems. Most of the diseases arechronically debilitating conditions, and some are life threat-ening. Their rarity and the phenotype variability imply lim-ited knowledge of the underlying mechanism(s) and natu-ral course, lack of standardization of diagnostic proceduresand fragmentation of the clinical and biological data col-lections, with small cohorts restricting the power of clinicalstudies [3,4]. Furthermore, the low prevalence implies alack of priority for the pharmaceutical industry and evenpublic funding [5]. The establishment of multidisciplinaryprojects gathering a critical mass of expertise and patients,at the European level, is thus essential to maximize theimpact of research on rare diseases [3].

EUNEFRON (the European Network for the Study ofOrphan Nephropathies) is a consortium that has been mobi-lized in response to the Call HEALTH-2007-2.4.4-1 (‘Nat-ural course and pathophysiology of rare diseases princi-pally affecting the genitourinary tract’) of the framework 7(FP7) programme for health of the European Union. Theresearch programme, which involves 12 research groupsfrom 10 academic institutions in 8 European countries(Figure 1), has been launched on 1 May 2008, for an initialduration of 4 years and with a total budget of 6 millioneuros.

Rationale and aims of the EUNEFRONconsortium

Despite significant research efforts, our understanding ofthe natural course and pathophysiology of rare inheriteddiseases of the kidney remains limited. Some of the genesmutated in these diseases are involved in renal structureand function, but we know much less about the regulatorypathways they act in or about the molecular and cellularmechanisms that cause their malfunction in renal disease.As a result, little progress has been made towards improveddiagnosis and therapy of these conditions. Although indi-vidual areas of expertise in rare diseases exist in Europe, in-sufficient coordination between groups and fields may posea threat to the understanding of such conditions, both at theclinical and mechanistic level, delaying the development ofnovel diagnostic and therapeutic tools. Accordingly, thereis a growing interest in coordinating research and collectinginformation pertinent to rare inherited nephropathies acrossEurope [3–5].

The aim of EUNEFRON is to mobilize a critical mass ofexpertise to investigate, on a Europe-wide scale, the naturalhistory and pathophysiology of a series of rare inherited dis-eases of the kidney. The project will exploit the technologi-cal opportunities of the post-genome era and the knowledgegenerated through existing networks and projects funded bythe FP6, including EuReGene, the European Renal Genomeproject [5]. In particular, EUNEFRON will use in vitro andin vivo models to pursue specific objectives in 16 diseasesaffecting the glomerulus, the proximal tubule (PT), the thickascending limb (TAL), the distal convoluted tubule (DCT)and the collecting duct (CD) (Figure 2). These diseases arecaused by mutations in 20 genes that encode proteins in-volved in a wide range of functions, including enzymatic ac-tivities, transport mechanisms, structure and transcriptional

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NDT Advance Access published March 4, 2009

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Fig. 1. EUNEFRON: Geographic distribution of the 10 participating academic institutions (12 research groups) in 8 European countries.

Fig. 2. Details of the 16 rare inherited nephropathies that are investigated in EUNEFRON, grouped by segment/topic. These diseases are caused bymutations in 20 genes (indicated in italics) that encode proteins involved in a wide range of functions (enzyme, transport, structure, transcription, etc.).

Nephrol Dial Transplant (2009) 3

Fig. 3. Structure of the EUNEFRON project. Studies in Topics 1 to 5will provide insights into the natural course and pathophysiology of therare nephropathies. Topic 6 will integrate the relevant information into aregistry, while establishing a network of genetic laboratories. The man-agement and dissemination activities (Topic 7) provide constant supportfor the research activities and dissemination of knowledge.

regulation. The proposal also aims at initiating a Euro-pean registry and a network of genetic laboratories to fosterinteractions between physicians and researchers, promoteclinical and basic research and ensure efficient diagnosticprocedures. It includes a comprehensive strategy of dis-semination, involving patient organizations and experts inethics and socio-economics, biobanking and drug develop-ment. By increasing our knowledge of these rare diseases,EUNEFRON should help to develop preventive, diagnosticand therapeutic interventions for these rare diseases andyield new insights into renal disease progression, bloodpressure control, prevention of renal stones, effect of gen-der and ageing and multi-systemic involvement of renaldiseases.

Overall structure of the programme

The EUNEFRON consortium integrates experts in genet-ics, clinical nephrology (adult and pediatric), physiologyand cell/molecular biology from 12 research groups. Theuse and development of disease models, including trans-genic mice and model organisms such as the Xenopus laevistadpole, the expertise in genetics and phenotype character-ization and the availability of registries and cohorts wereconsidered crucial for this programme. The specific objec-tives are organized in five topics according to the nephronsegment concerned. The data generated in these topics willbe integrated in a registry, and a network of genetic laborato-ries will be implemented. Management and disseminationwill support all activities within the consortium and willprovide support for dissemination of knowledge (Figure 3).The topic coordinators and the project coordinator formthe Steering Committee of the programme, which is sup-ported by the Project management office and by Panels setup for ethics/society, training and exploitation/intellectual

property rights (IPR). An external Advisory Board providesguidance to the Steering Committee. All principal investi-gators in EUNEFRON constitute the General Assembly, theultimate decision-making body of the programme.

Specific objectives of EUNEFRON

Disorders of the glomerulus

This topic is focused on rare diseases affecting the podocyte,including steroid-resistant nephrotic syndrome caused bymutations in NPHS2, the gene coding for podocin [6],and fetomaternal alloimmunization with antenatal glomeru-lopathy (FMAIG), an alloimmune disorder resulting frommaternal antibodies directed against neutral endopepti-dase that cross the placenta and bind to fetal glomeru-lar podocytes [7]. These disorders provide the opportunityto analyse ‘pure’ podocyte pathobiology, irrespective ofconfounding factors. We will also investigate the pathogen-esis of disorders due to defective type IV collagen, includ-ing Alport syndrome [8] and the newly described Heredi-tary Angiopathy with Nephropathy, Aneurism and Cramps(HANAC) syndrome [9], as well as therapeutic modalitiesin Fabry Disease [10].

Disorders of the proximal tubule

We will use cell and mouse models and registries to inves-tigate cystinosis, the most common inherited type of renalFanconi syndrome. Cystinosis is an autosomal recessivedisorder characterized by defective lysosomal efflux of cys-tine, caused by inactivating mutations in the CTNS gene thatencodes the cystine transporter cystinosin [11]. In particu-lar, we will seek to understand the influence of lysosomalcystine accumulation on PT cell phenotype, including ox-idative stress and adaptation to specific therapies. We willalso investigate disorders affecting the endocytic activity ofPT cells, including Dent’s disease, a X-linked form of renalFanconi syndrome associated with hypercalciuria, kidneystones and progressive renal failure, caused by mutationsin the CLCN5 gene coding for the endosomal Cl−–H+ ex-changer ClC-5 [12,13]. Other disorders with defective PTendocytosis include cystic fibrosis, due to recessive muta-tions in the CFTR Cl− channel [14]; Imerslund Grasbeckdisease, a rare autosomal recessive disorder caused by vi-tamin B12 (cobalamin) malabsorption with tubular protein-uria, caused by mutations in the cubilin (CUBN) or amnion-less (AMN) genes that code for endocytic receptors locatedin intestine and PT cells [15] and Maturity Onset Diabetesof the Young (MODY3), an autosomal dominant form ofdiabetes caused by heterozygous mutations in TCF1, a genethat encodes the transcription factor HNF1α [16]. This topicwill also address the tubular component of the basalopathyassociated with HANAC [9].

Disorders of the thick ascending limb of Henle’s loop

We will develop novel mouse models and cell culture sys-tems to provide insights into disorders of the TAL, in-cluding familial hypomagnesaemia with hypercalciuria and

4 Nephrol Dial Transplant (2009)

nephrocalcinosis (FHHNC), caused by mutations in theCLDN16 and CLDN19 genes coding for the tight junc-tion proteins claudin-16 and claudin-19 [17,18], and famil-ial juvenile hyperuricemic nephropathy (FJHN, also namedmedullary cystic kidney disease type 2, MCKD2). FJHN iscaused by mutations in UMOD, the gene encoding Tamm–Horsfall protein (uromodulin), the most abundant proteinin the normal urine [19,20]. Mutations in uromodulin leadto its intracellular accumulation, followed by interstitialnephritis and tubular damage [20]. A better understandingof these mechanisms is relevant for urinary concentrationdefects, interstitial nephritis and kidney stones [21].

Disorders of the distal convoluted tubule

This topic will investigate the pathophysiology of Gitel-man’s syndrome (GS) and pseudohypoaldosteronism type II(PHA2, or Gordon syndrome). GS is an autosomal recessivedisorder causing salt wasting and secondary aldosteronism,with hypomagnesaemia and hypocalciuria, due to inactivat-ing mutations in SLC12A3 that codes for the Na+–Cl− co-transporter NCCT [22,23]. PHA2 is an autosomal dominantdisorder characterized by hypertension and hyperkalaemia,i.e. a phenotype that is opposite to GS [24]. Mutations in twomembers of the WNK kinase family, WNK1 and WNK4,have been involved in PHA2 through their coordinated reg-ulation of NCCT [25]. These investigations will yield newdisease models and insights into regulation of blood pres-sure, response to diuretics and transport mechanisms (e.g.Ca2+ and Mg2+ handling) in the DCT [26,27].

Disorders of the collecting duct

The CD consists of principal cells and intercalated cellsthat play essential roles in fine-tuning the sodium/water andacid–base homeostasis, respectively. Mutations in AVPR2and AQP2 genes that encode the vasopressin type 2 re-ceptor (V2R) and the aquaporin-2 (AQP2) water channel,respectively, cause nephrogenic diabetes insipidus (NDI), adisorder in which the antidiuretic response to vasopressinis lacking, resulting in polyuria and polydipsia [28]. An-ion exchanger proteins (AE1, pendrin) and vacuolar H+-ATPase control blood pH and cause distal renal tubularacidosis (dRTA) when mutated [29,30]. We will investigatethe genotype–phenotype correlations and the molecular ba-sis underlying dRTA and study the role and interactions ofpendrin, AE1 interacting proteins and ammonium trans-porters [31]. Patients with NDI will be analysed, and wewill test whether V2R (ant)agonists are able to rescue theirencoded V2R mutants [32].

Registry and network of genetic laboratories

Rare diseases show a significant phenotypic and geneticheterogeneity, which hampers their clinical characteriza-tion and the initiation of therapeutic trials. The collabora-tion of expert clinical centres in EUNEFRON will facilitatethe centralization of clinical and biological informationbased on a large recruitment of patients through the cre-ation of a European registry and a network of genetic lab-oratories [3,4]. The registry will be a critical tool to im-

prove our knowledge of the natural course of the disease;to facilitate the dissemination of information; to promotebasic and clinical investigations and to improve clinicalcare and follow-up of the patients. As part of this pro-gramme, we will extend the UK Cystinosis Registry toother European centres, with special attention to genderand ageing aspects, effect of cysteamine and additive ther-apies. Initiating a European network of genetic laboratoriesshould improve the procedures for genetic diagnosis, sim-plify access to genotyping and facilitate the search for newgenes.

Dissemination of knowledge through EUNEFRON

EUNEFRON will organize public symposia on rare inher-ited nephropathies (the first scheduled in Zurich, 18 April2009; see www.eunefron.org), training courses coveringstrategic technologies and short-term fellowships for sci-entists. Participants will get training on IPR, gender issuesin research and ethics and social issues in rare diseases.The programme has created a website (www.eunefron.org)which facilitates contacts between partners and containsinformation relevant to the outside scientific community,including the scientific projects, the diseases investigated,repositories (animal models, cell lines), novel tools (an-tibodies, probes) and methodologies and the registry andthe network of genetic laboratories. The website will alsoinform about educational activities and will contain infor-mation relevant to patient advocacy groups, healthcare pro-fessionals, the legislature and the interested public. All ac-tivities within the consortium are linked to national andEuropean initiatives (e.g. Orphanet) in the area of rare dis-eases. Interested physicians and health care professionalsare invited to contact consortium members for patient re-ferrals or additional information.

Expected results

After 4 years, the work programme of EUNEFRONshould bring novel discovery tools including modelorganisms, transgenic mice and cell culture systems.These tools will provide insights into the natural course,genotype–phenotype correlations and pathophysiology ofrare nephropathies, with relevance for acquired renal dis-eases and multi-systemic complications, providing new tar-gets for diagnosis and therapeutic intervention. Initiation ofa registry will facilitate the translation of insights into pa-tient care, by improving phenotype standardization and fos-tering studies of the natural course and genotype–phenotypecorrelations on a Europe-wide scale. Similarly, a networkof genetic laboratories should facilitate access to genotyp-ing, standardize and improve the procedures and pave theway for new gene discovery. These new tools will be ac-cessible throughout the scientific and health care commu-nity in accordance with the ethical guidelines. The web-site, educational activities and exchanges organized throughEUNEFRON should increase the awareness of patients,health care providers and scientists for rare inheritednephropathies in Europe.

Nephrol Dial Transplant (2009) 5

Acknowledgements. The authors acknowledge the EuReGene (FP6,GA#5085)) and EUNEFRON (FP7, GA#201590) programs of theEuropean Community.

Conflict of interest statement. None declared.

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Received for publication: 10.2.09; Accepted in revised form: 16.2.09