Molecular Genetics of Kidney Development and Congenital Anomalies (Dr. Lu)

The long-term goal of our research is to understand the molecular basis of congenital anomalies of the kidney and urinary tract (CAKUT). CAKUT is a family of diseases with a diverse anatomical spectrum, including kidney anomalies (e.g. renal dysplasia, duplex kidney, multicystic kidney, hydronephrosis), and ureteric anomalies (e.g. vesicoureteral reflux, megaureter, ureterovesical and ureteropelvic junction obstruction). CAKUT results from abnormal early kidney development and has been suggested to be inherited as a polygenic trait with incomplete and variable penetrance. Vesicoureteral reflux (VUR) is a common clinical finding of CAKUT. It is one of the commonest genetic disorders found in children, with an incidence of approximately 1 in 100 infants. VUR is found in 30-50% of infants and young children with a urinary tract infection (UTI). These patients may present later in life with proteinuria, hypertension and reflux nephropathy (RN), which account for 15% of end-stage renal disease. Primary VUR results from an anatomic deformity of the ureterovesical junction (UVJ) and is known to occur in families. Despite the high incidence of VUR in the pediatric population, the genetic basis of VUR remains unknown. The current research activities in the lab are to identify and define the role of several key genetic determinants in kidney development and mutations that cause CAKUT and VUR.
We have adopted human and mouse molecular genetics approaches and identified a number of developmental genes (e.g. ROBO2 and NFIA) that are critical for kidney and ureteral development, and found that disruption of these genes is associated with CAKUT and VUR in human and mouse. The first human molecular genetics approach is to study individuals with CAKUT and VUR and apparent balanced chromosomal rearrangements, with the aim of using balanced chromosomal rearrangements as signposts to identify these developmental genes. Chromosomal breakpoints were analyzed to identify single BAC clones containing relevant candidate genes. Molecular identification and analysis of these candidate gene as well as mutation studies in affected individuals with a familial pattern of CAKUT and VUR have been carried out. The second approach is to study temporal and spatial expression patterns of these candidate genes during human and mouse development. Meanwhile, we have generated and are currently analyzing several conventional and conditional knockout and transgenic mouse models of these genes to elucidate more fully their role in kidney and ureteral development and in the pathogenesis of CAKUT and VUR.


  1. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet 2003; 33(2):129-137
  2. Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D, Axelrod FB, Maayan C, Gusella JF, Slaugenhaupt SA. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am J Hum Genet 2003; 72(3):749-758
  3. Hughes P, Robati M, Lu W, Zhou J, Strasser A, Bouillet P. Loss of PKD1 and loss of Bcl-2 elicit polycystic kidney disease through distinct mechanisms. Cell Death and Differentiation 2006; 13(7):1123-1127
  4. Wilson SJ, Amsler K, Hyink DP, Li X, Lu W, Zhou J, Burrow CR, Wilson PD. Inhibition of HER-2(neu/ErbB2) restores normal function and structure to polycystic kidney disease (PKD) epithelia. Biochim Biophys Acta 2006; 1762(7):647-655
  5. Lu W, van Eerde AM, Fan X, Quintero-Rivera F, Kulkarni S, Ferguson HL, Kim H, Fan Y, Xi Q, Li QG, Sanlaville D, Andrews W, Sundaresan V, Bi W, Yan J, Giltay JC, Wijmenga C, de Jong TPVM, Feather S, Woolf A, Rao Y, Lupski JR, Eccles MR, Quade BJ, Gusella JF, Morton CC, Maas RL. Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. Am J Hum Genet 2007; 80(4):616-632
  6. Leach NT, Sun Y, Michaud S, Zheng Y, Ligon KL, Ligon AH, Korf BR, Lu W, Harris DJ, Gusella JF, Maas RL, Quade BJ, Cole AJ, Kelz MB, Morton CC. Disruption of diacylglycerol kinase delta in association with seizures and vascular abnormalities. Am. J. Hum. Genet 2007; 80(4):792-799
  7. Lu W, Quintero-Rivera F, Fan Y, Alkuraya F, Donovan DJ, Xi Q, Turbe-Doan A, Li QG, Campbell CG, Shanske AL, Sherr EH, Ahmad A, Peters R, Rilliet B, Parvex P, Bassuk AG, Harris DJ, Ferguson H, Kelly C, Walsh CA, Gronostajski RM, Devriendt K, Higgins A, Ligon AH, Quade BJ, Morton CC, Gusella JF, Maas RL. NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects, PLoS Genet 2007; 3(5):e80:0830-0843
  8. Higgins AW, Alkuraya FS, Bosco AF, Bruns GAP, Donovan DJ, Eisenman R, Fan Y, Farra CG, Ferguson HL, Gusella JF, Harris DJ, Herrick SR, Kelly C, Kim HG, Kishikawa S, Kocher KM, Korf BR, Kulkarni S, Leach NT, Lemyre E, Lewis J, Ligon AH, Lu W, Maas RL, MacDonald ME, Moore SDP, Peters RE, Quade BJ, Quintero-Rivera F, Saadi I, Shen Y, Shendure J, Williamson RE, Morton CC. Characterization of Apparently Balanced Chromosomal Rearrangements from the Developmental Genome Anatomy Project. Am. J. Hum. Genet 2008; 82(3):712-722