Elsevier

Kidney International

Volume 85, Issue 6, June 2014, Pages 1310-1317
Kidney International

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

https://doi.org/10.1038/ki.2013.417Get rights and content
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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 receptorassociated 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 VACTERL association with CAKUT.

Keywords

genetics and development
genetic renal disease
renal agenesis
renal development
ureteric bud
vesicoureteral reflux

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All the authors declared no competing interests.

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These authors contributed equally to this work.