1. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association.
- Author
-
Saisawat P, Kohl S, Hilger AC, Hwang DY, Yung Gee H, Dworschak GC, Tasic V, Pennimpede T, Natarajan S, Sperry E, Matassa DS, Stajić N, Bogdanovic R, de Blaauw I, Marcelis CL, Wijers CH, Bartels E, Schmiedeke E, Schmidt D, Märzheuser S, Grasshoff-Derr S, Holland-Cunz S, Ludwig M, Nöthen MM, Draaken M, Brosens E, Heij H, Tibboel D, Herrmann BG, Solomon BD, de Klein A, van Rooij IA, Esposito F, Reutter HM, and Hildebrandt F
- Subjects
- Age Factors, Animals, Europe, Female, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Gestational Age, Heart Defects, Congenital diagnosis, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Kidney embryology, Kidney metabolism, Limb Deformities, Congenital diagnosis, Male, Mice, Multiplex Polymerase Chain Reaction, Pedigree, Predictive Value of Tests, Risk Factors, United States, Urogenital Abnormalities, Vesico-Ureteral Reflux diagnosis, Anal Canal abnormalities, DNA Mutational Analysis methods, Esophagus abnormalities, Exosomes, Genetic Testing methods, HSP90 Heat-Shock Proteins genetics, HSP90 Heat-Shock Proteins metabolism, Heart Defects, Congenital genetics, Kidney abnormalities, Limb Deformities, Congenital genetics, Mutation, Spine abnormalities, Trachea abnormalities, Vesico-Ureteral Reflux genetics
- 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 VACTERL association with CAKUT.
- Published
- 2014
- Full Text
- View/download PDF