title: 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 VACTERL association with CAKUT.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pawaree
authors.initials: P
authors.lastname: Saisawat
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: 1] Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heon
authors.initials: H
authors.lastname: Yung Gee
authors.affiliation: 1] Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Dworschak
authors.affiliation: Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Tracie
authors.initials: T
authors.lastname: Pennimpede
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Natarajan
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Sperry
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Danilo S
authors.initials: DS
authors.lastname: Matassa
authors.affiliation: 1] Medical Faculty, University of Belgrade, Belgrade, Serbia [2] Institiute of Mother and Child Healthcare of Serbia, Belgrade, Serbia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Stajić
authors.affiliation: 1] Medical Faculty, University of Belgrade, Belgrade, Serbia [2] Institiute of Mother and Child Healthcare of Serbia, Belgrade, Serbia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.affiliation: Department of Pediatric Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: de Blaauw
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Carlo L M
authors.initials: CL
authors.lastname: Marcelis
authors.affiliation: Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Charlotte H W
authors.initials: CH
authors.lastname: Wijers
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Enrika
authors.initials: E
authors.lastname: Bartels
authors.affiliation: Department of Pediatric Surgery and Urology, Center for Child and Adolescent Health, Hospital Bremen-Mitte, Bremen, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schmiedeke
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Pediatric Surgery, Campus Virchow Clinic, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Department of Pediatric Surgery, Campus Virchow Clinic, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Märzheuser
authors.affiliation: Department of Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grasshoff-Derr
authors.affiliation: Department of Pediatric Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holland-Cunz
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Draaken
authors.affiliation: 1] Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands [2] Department of Clinical Genetics, Erasmus MC-Sophia, Rotterdam, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: Brosens
authors.affiliation: Pediatric Surgical Center of Amsterdam, Emma Children's Hospital and VuMC, Amsterdam, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: Heij
authors.affiliation: Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: Department of Clinical Genetics, Erasmus MC-Sophia, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.affiliation: Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Iris A L M
authors.initials: IA
authors.lastname: van Rooij
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Reutter
authors.affiliation: 1] Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000367:Age Factors; D001003:Anal Canal / Q000002:abnormalities*; D000818:Animals; D004252:DNA Mutational Analysis / Q000379:methods; D004947:Esophagus / Q000002:abnormalities*; D005060:Europe; D055354:Exosomes; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005865:Gestational Age; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D010375:Pedigree; D011237:Predictive Value of Tests; D012307:Risk Factors; D013131:Spine / Q000002:abnormalities*; D014132:Trachea / Q000002:abnormalities*; D014481:United States; D014564:Urogenital Abnormalities; D014718:Vesico-Ureteral Reflux / Q000175:diagnosis / Q000235:genetics*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C547760:TRAP-1 protein, mouse; C092306:TRAP1 protein, human; C549284:TRAP1 protein, rat