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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK088767-01
Application #
7940309
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
2010-07-05
Project End
2014-06-30
Budget Start
2010-07-05
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$381,890
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
van der Ven, Amelie T; Vivante, Asaf; Hildebrandt, Friedhelm (2018) Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol 29:36-50
Warejko, Jillian K; Schueler, Markus; Vivante, Asaf et al. (2018) Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ?43% of 35 Families With Midaortic Syndrome. Hypertension 71:691-699
van der Ven, Amelie T; Connaughton, Dervla M; Ityel, Hadas et al. (2018) Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol 29:2348-2361
Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802
van der Ven, Amelie T; Shril, Shirlee; Ityel, Hadas et al. (2017) Whole-Exome Sequencing Reveals FAT4 Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report. Mol Syndromol 8:272-277
Vivante, Asaf; Ityel, Hadas; Pode-Shakked, Ben et al. (2017) Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases. Pediatr Nephrol 32:2273-2282
Vivante, Asaf; Mann, Nina; Yonath, Hagith et al. (2017) A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling. J Am Soc Nephrol 28:2364-2376
Vivante, Asaf; Hwang, Daw-Yang; Kohl, Stefan et al. (2017) Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract. J Am Soc Nephrol 28:69-75
Reutter, Heiko; Hilger, Alina C; Hildebrandt, Friedhelm et al. (2016) Underlying genetic factors of the VATER/VACTERL association with special emphasis on the ""Renal"" phenotype. Pediatr Nephrol 31:2025-33
Kohl, Stefan; Chen, Jing; Vivante, Asaf et al. (2016) Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract. Nephrol Dial Transplant 31:1280-3

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