Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Abstract

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association.

Genetics of Congenital Anomalies of the Kidneys and Urinary Tract

“…Consequently, combining whole exome sequencing (WES) with genetic mapping strategies [ 21 ] enables identifi cation of disease genes in those rare monogenic causes of CAKUT. For instance, application of homozygosity mapping has permitted us to identify recessive CAKUT causing genes [ 26 ].…”

Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development

“…2,11 (2) By devising a high-throughput exon sequencing technique, 12 we previously showed that causative mutations in 12 different genes can be identified in about 10% of case subjects with CAKUT. [6][7][8] However, extensive genetic heterogeneity has rendered gene discovery in CAKUT very difficult. 7,8,10 Most known single genes that cause CA-KUT if mutated are inherited in an autosomal-dominant manner and exhibit the clinical genetic features of incomplete penetrance and variable expressivity.…”

“…Recent identification of monogenic mutations in genes that govern normal renal development permitted first insights into the pathomechanisms underlying some of these disorders in humans. [5][6][7][8][9] It has been hypothesized that many forms of CAKUT in humans are probably caused by rare single-gene defects, 10 based on multiple lines of evidence. (1) A large number of monogenic mouse models of CAKUT were reported, 10 and many of the related genes participate in nephrogenesis.…”

Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract

“…2 However, several CAKUT-causing genes with autosomal recessive mode of inheritance have been recently identified. 5,9,10 Nevertheless, in the clinical practice, the genetic basis of most patients with CAKUT is elusive because of a very weak genotypephenotype correlation. To determine the likelihood of detecting causative recessive mutations in CAKUT by whole-exome sequencing (WES), we have analyzed individuals with CAKUT from 33 consanguineous families.…”