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

• Published in: Kidney international Vol. 85; no. 6; pp. 1310 - 1317
• Main Authors: Saisawat, Pawaree, Kohl, Stefan, Hilger, Alina C., Hwang, Daw-Yang, Yung Gee, Heon, Dworschak, Gabriel C., Tasic, Velibor, Pennimpede, Tracie, Natarajan, Sivakumar, Sperry, Ethan, Matassa, Danilo S., Stajić, Nataša, Bogdanovic, Radovan, de Blaauw, Ivo, Marcelis, Carlo L.M., Wijers, Charlotte H.W., Bartels, Enrika, Schmiedeke, Eberhard, Schmidt, Dominik, Märzheuser, Stefanie, Grasshoff-Derr, Sabine, Holland-Cunz, Stefan, Ludwig, Michael, Nöthen, Markus M., Draaken, Markus, Brosens, Erwin, Heij, Hugo, Tibboel, Dick, Herrmann, Bernhard G., Solomon, Benjamin D., de Klein, Annelies, van Rooij, Iris A.L.M., Esposito, Franca, Reutter, Heiko M., Hildebrandt, Friedhelm
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2014; Elsevier Limited
• Subjects: Age Factors; Anal Canal - abnormalities; Animals; DNA Mutational Analysis - methods; Esophagus - abnormalities; Europe; Exosomes; Female; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; genetic renal disease; Genetic Testing - methods; genetics and development; Gestational Age; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; High-Throughput Nucleotide Sequencing; Homozygote; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Kidney - abnormalities; Kidney - embryology; Kidney - metabolism; Limb Deformities, Congenital - diagnosis; Limb Deformities, Congenital - genetics; Male; Mice; Multiplex Polymerase Chain Reaction; Mutation; Pedigree; Predictive Value of Tests; renal agenesis; renal development; Risk Factors; Spine - abnormalities; Trachea - abnormalities; United States; ureteric bud; Urogenital Abnormalities; Vesico-Ureteral Reflux - diagnosis; Vesico-Ureteral Reflux - genetics; vesicoureteral reflux; United States; Europe; genetics and development; ureteric bud; renal development; vesicoureteral reflux; renal agenesis; genetic renal disease
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2013.417

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 VACTERL association with CAKUT.