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Kidney Int. 2014 Jun;85(6):1310-7. doi: 10.1038/ki.2013.417. Epub 2013 Oct 23.

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

Author information

1
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
2
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
1] Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
4
1] Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
5
Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia.
6
Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
7
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
8
1] Medical Faculty, University of Belgrade, Belgrade, Serbia [2] Institiute of Mother and Child Healthcare of Serbia, Belgrade, Serbia.
9
Department of Pediatric Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
10
Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
11
Department for Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
12
Institute of Human Genetics, University of Bonn, Bonn, Germany.
13
Department of Pediatric Surgery and Urology, Center for Child and Adolescent Health, Hospital Bremen-Mitte, Bremen, Germany.
14
1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Pediatric Surgery, Campus Virchow Clinic, Charité University Hospital Berlin, Berlin, Germany.
15
Department of Pediatric Surgery, Campus Virchow Clinic, Charité University Hospital Berlin, Berlin, Germany.
16
Department of Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
17
Department of Pediatric Surgery, University of Heidelberg, Heidelberg, Germany.
18
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
19
1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
20
1] Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands [2] Department of Clinical Genetics, Erasmus MC-Sophia, Rotterdam, The Netherlands.
21
Pediatric Surgical Center of Amsterdam, Emma Children's Hospital and VuMC, Amsterdam, The Netherlands.
22
Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands.
23
Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
24
Department of Clinical Genetics, Erasmus MC-Sophia, Rotterdam, The Netherlands.
25
1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
26
1] Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

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.

PMID:
24152966
PMCID:
PMC3997628
DOI:
10.1038/ki.2013.417
[Indexed for MEDLINE]
Free PMC Article

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