New genes and pathomechanisms of congenital anomalies of the kidney (CAKUT). Chronic kidney diseases (CKD) take a high toll on human health, requiring dialysis or kidney transplantation for survival. In the first 2 decades of life ~0% of CKD is caused by CAKUT. However, very little is known about its etiology and pathogenesis. No curative treatment or prophylaxis is available. We identified novel single-gene causes of CAKUT in mutations of the genes SIX1, SIX5 and TRAP1 (PNAS 2004; AJHG 2007; JASN 2013). Recently, we showed that >10% of CAKUT is 'monogenic' in origin, being caused by mutations in one of >21 different genes (KI 85:1429, 2014). Other groups revealed a CNV disorder in ~15% of CAKUT (AJHG 91:987, 2012). Using genetic mapping, whole exome sequencing (WES) and high-throughput candidate gene analysis, we identified very recently 11 novel single-gene causes of isolated CAKUT: FRAS1, FREM2, GRIP1, FREM1, GREM1, ITGA8, TRAP1, SRGAP1, SLIT2, TBX18, and TSHZ3. Single-gene causes have started to coalesce around distinct signaling pathways, including FRAS-FREM signaling, ROBO2-SLIT2-SRGAP1 signaling, and differentiation of ureteric smooth muscle (TBX18 and TSHZ3), thus elucidating the pathogenesis of CAKUT. Our data demonstrate that: i) a high percentage of CAKUT is caused by single-gene mutations in a multitude of genes, ii) several dozen single-gene causes of CAKUT are yet to be identified, iii) WES, and a high-throughput candidate sequencing that we developed very efficiently reveal novel disease genes and developmental pathways that are involved in the pathogenesis of human CAKUT. From these data we hypothesize that single-gene mutations in many distinct unidentified genes will represent novel monogenic causes of CAKUT, and that gene identification will allow delineation of further disease mechanisms of CAKUT. To this end we now: 1) Ascertained >2,400 families with CAKUT, 2) Developed rapid sequencing to identify mutations in CAKUT candidate genes, and 3) Performed linkage mapping in 140 CAKUT families from the US, India and Kuwait. We will now employ WES in 480 sib cases and 40 consanguineous CAKUT families and apply our newly developed high-throughput sequencing approaches to the identification and pathogenic characterization of novel CAKUT-causing genes, with the specific aims: 1. Identify novel full-penetrance recessive causes of CAKUT by genetic mapping and whole exome sequencing in 520 families. 2. Identify novel causes of CAKUT by high-throughput candidate gene analysis and study genotype-phenotype correlations in large molecularly defined cohorts. 3. Delineate disease mechanisms of CAKUT by further characterizing genetic defects of the newly implicated SLIT2-ROBO2-SRGAP1 and TBX18-THSZ3 pathways. Gene identification is a prerequisite to address prevention of this predominating cause of early-onset CKD.
Novel single-gene causes and disease mechanisms of CAKUT. Chronic kidney diseases (CKD) take one of the highest tolls on human health, requiring dialysis or kidney transplantation for survival. In the first 2 decades of life ~50% of CKD is caused by Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). However, very little is known about the etiology and pathogenesis of CAKUT. No curative treatment or prophy- laxis is available. Using high-throughput sequencing techniques we and others showed recently that at least 10% of all forms of CAKUT can be attributed to single-gene defects in two dozen different genes. Our data demonstrate that there are several dozen additional single-gene causes of CAKUT yet to be identified, and that gene identification allows insights into the mechanisms by which CAKUT arises. We propose here to: 1. Identify novel full-penetrance recessive causes of CAKUT by genetic mapping and whole exome sequencing in 140 families. 2. Identify novel causes of CAKUT by high-throughput candidate gene analysis and study genotype-phenotype correlations in large molecularly defined cohorts. 3. Delineate disease mechanisms of CAKUT by further characterizing genetic defects of the newly implicated SLIT2-ROBO2-SRGAP1 and TBX18-THSZ3 pathways. Gene identification will allow delineation of disease mechanisms in CAKUT, which may then be addressed for prevention of this predominant cause of early-onset CKD.
Showing the most recent 10 out of 31 publications
