New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT). Chronic kidney diseases (CKD) take one of the highest tolls on human health, requiring dialysis or kidney transplantation for survival. Congenital abnormalities of the kidney and urinary tract (CAKUT) constitute the most frequent cause of CKD in children, accounting for ~50% of all cases. We identified previously, by positional cloning, 2 novel dominant single-gene causes of CAKUT (Ruf PNAS 101:890, 2004;Hoskins AJHG 80:800, 2007). We, now, recruited genomic DNA and clinical data in a multi-ethnic cohort of children with CAKUT from 456 different families, and generated preliminary data by total genome homozygosity mapping that demonstrate the presence of recessive single-gene loci in sib ships and single cases with non-syndromic CAKUT. We also established a new technology of exome capture with consecutive large-scale sequencing for the identification of novel single-gene causes of CAKUT. In 20 sib ships we mapped 1 new locus and several putative loci, which are homozygous by descent, as strong candidate loci for causative recessive mutations in unidentified genes. From these data and from animal models of CAKUT we hypothesize that single-gene mutations in many distinct unidentified genes, both recessive and dominant, will represent novel causes of CAKUT. We will now employ our newly established method of homozygosity mapping with exon capture and consecutive large- scale sequencing to identify and functionally characterize novel CAKUT-causing genes. We will pursue the following aims: 1. Identify novel recessive causes of CAKUT by homozygosity mapping, exon capture, and large-scale (LS) sequencing in families with homozygosity by descent. 2. Identify novel dominant causes of CAKUT by 2.1M Whole Human Exome Capture and LS sequencing. 3. Functionally characterize the newly identified CAKUT genes in zebrafish models.
Congenital abnormalities of the kidney and urinary tract (CAKUT) account for about ~50% of chronic kidney disease in children. No prophylaxis or curative treatment is available. Although many forms of CAKUT are very likely caused by single-gene defects, only few causative genes have been identified so far. We recently established a new approach of homozygosity mapping, exon capture and large-scale sequencing for identification of new CAKUT-causing genes. We will apply these new approaches to a worldwide cohort of 456 families with CAKUT, which we have recruited. The identification of new single-gene causes of SRNS will: i) lead to identification of novel single-genes causes of CAKUT;ii) introduce the new technologies of exon capture and large-scale sequencing into the diagnostics of CAKUT;iii) permit early, unequivocal molecular genetic diagnostics;iv) help unravel the disease mechanisms of CAKUT;v) allow detailed mechanistic studies of the pathomechanisms of CAKUT in zebrafish models;vi) permit development of zebrafish model systems for high-throughput drug screening for this disease.
|Vivante, Asaf; Kohl, Stefan; Hwang, Daw-Yang et al. (2014) Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol 29:695-704|
|Slaats, Gisela G; Ghosh, Amiya K; Falke, Lucas L et al. (2014) Nephronophthisis-associated CEP164 regulates cell cycle progression, apoptosis and epithelial-to-mesenchymal transition. PLoS Genet 10:e1004594|
|Kohl, Stefan; Hwang, Daw-Yang; Dworschak, Gabriel C et al. (2014) Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol 25:1917-22|
|Hwang, Daw-Yang; Dworschak, Gabriel C; Kohl, Stefan et al. (2014) Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int 85:1429-33|
|Saisawat, Pawaree; Kohl, Stefan; Hilger, Alina C et al. (2014) Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int 85:1310-7|
|Hilger, Alina; Schramm, Charlotte; Pennimpede, Tracie et al. (2013) De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association. Eur J Hum Genet 21:1377-82|
|Saisawat, Pawaree; Tasic, Velibor; Vega-Warner, Virginia et al. (2012) Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis. Kidney Int 81:196-200|
|Beck, Bodo B; Trachtman, Howard; Gitman, Michael et al. (2011) Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD. Am J Kidney Dis 58:821-5|
|Zhou, Weibin; Boucher, Rudrick C; Bollig, Frank et al. (2010) Characterization of mesonephric development and regeneration using transgenic zebrafish. Am J Physiol Renal Physiol 299:F1040-7|