E-Mail karger@karger.com Experimental Nephrology: Review Nephron DOI: 10.1159/000369313 Functional Models for Congenital Anomalies of the Kidney and Urinary Tract Glenn van de Hoek a, b Nayia Nicolaou a Rachel H. Giles b Nine V.A.M. Knoers a Kirsten Y. Renkema a Ernie M.H.F. Bongers c a Department of Medical Genetics, Center for Molecular Medicine, b Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, and c Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands lead to congenital anomalies of the kidney and urinary tract (CAKUT). The molecular mechanisms underlying human embryonic kidney and urinary tract develop- ment, including the processes that may lead to malforma- tion, have been extensively reviewed [1]. In brief, human kidney development proceeds through three stages: the pronephros, mesonephros, and metanephros. Both the pronephros and mesonephros are transient structures and although they do not contribute structurally to the eventual metanephros, they do provide inductive signals for adult kidney development [2]. Coordinated interac- tions between the early nephrotic tissues are fundamental to ureteric budding, epithelial branching, mesenchymal to epithelial transformation, morphogenesis, and differ- entiation. Although these processes are crucial for normal development of the kidneys and urinary tract, malfunc- tion of the same processes were shown to be involved in CAKUT [3]. The advent of next-generation sequencing (NGS) techniques has enabled extensive sequencing ef- forts in patients with renal disease to identify novel un- derlying molecular mechanisms [4] and has led to a pleth- ora of prospective CAKUT candidate genes. Proving cau- sality of the genetic variants identified, is one of the challenges in CAKUT research. Here, we summarize the models that are currently available and discuss what is Key Words CAKUT · Functional characterization · Gene · Kidney · Model system · Mutation Abstract Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common developmental diseases in humans; however, the cause for most patients remains un- known. Efforts to identify novel genetic causes for CAKUT through next-generation sequencing techniques have led to the discovery of new genes and risk factors. Concomitantly, these same efforts have generated large gene candidate lists requiring individual functional characterization. Appropriate model systems are needed to assess the functionality of genes and pathogenicity of genetic variants discovered in CAKUT patients. In this review, we discuss how cellular, animal, and personal (human) models are being used to study CAKUT can- didate genes and what their major advantages and disadvan- tages are with respect to relevance and throughput. © 2014 S. Karger AG, Basel Introduction The development of the renal system entails a complex process of interactions between tissues, genetic pathways, and environmental factors, which, when disturbed, can Received: September 8, 2014 Accepted after revision: October 24, 2014 Published online: December 19, 2014 Dr. Kirsten Y. Renkema Department of Medical Genetics, STR.1.305, University Medical Center Utrecht PO Box 85060 NL–3508 AB Utrecht (The Netherlands) E-Mail K.Renkema  @  umcutrecht.nl © 2014 S. Karger AG, Basel 1660–8151/14/0000–0000$39.50/0 www.karger.com/nef Glenn van de Hoek and Nayia Nicolaou contributed equally to this work. Downloaded by: University Library Utrecht 143.121.239.112 - 1/14/2015 9:19:06 AM