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.
Bibliographical noteFunding Information:
We thank the physicians and families for participating in this study, the German self-help organization for people with anorectal malformations (SoMA eV), and all participating physicians, nurses, research assistants, laboratory analysts, and project members of AGORA (Aetiologic research into Genetic and Occupational/Environmental Risk Factors for Anomalies in Children) for their support in building this biobank. FH is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and a Frederick GL Huetwell Professor. ACH, GCD, Enrika Bartels, ES, DS, SG-D, SM, SH-C, MMN, ML, HMR, and MD are members of the ‘Network for the Systematic Investigation of the Molecular Causes, Clinical Implications and Psychosocial Outcome of Congenital Uro-Rectal Malformations’ (CURE-Net). This research was supported by grants from the National Institutes of Health (to FH; R01-DK045345 and R01-DK088767), by the March of Dimes Foundation (6FY11-241), by the Division of Intramural Research, by the National Human Genome Research Institute (NHGRI), by the National Institutes of Health and Human Services, by the Bundesministerium für Bildung und Forschung (grant 01GM08107), by the BONFOR program of the University of Bonn (to Enrika Bartels; grant O-149.0099, and to GCD; grant O-149.0096), by Sophia Scientific Research Foundation (to Enrika Bartels; grant SSWO S13/9), by the associazione Italiana per la Ricerca sul Cancro (AIRC) (to FE; grant IG13128), and by the Italian Ministry of Health (to FE; grant GR-2010-2310057). Web Resources: 1000 Genomes Browser, http://browser.1000genomes.org ; Ensembl Genome Browser, http://www.ensembl.org ; Exome Variant Server, http://evs.gs.washington.edu/EVS ; Mutation Taster, http://www.mutationtaster.org ; Gudmap (GenitoUrinary Molecular Anatomy Project), http://www.gudmap.org ; Online Mendelian Inheritance in Man (OMIM), http://www.omim.org ; Polyphen2, http://genetics.bwh.harvard.edu/pph2 ; Sorting Intolerant From Tolerant (SIFT), http://sift.bii.a-star.edu.sg ; The Human Protein Atlas, http://www.proteinatlas.org ; UCSC Genome Browser, http://genome.ucsc.edu/cgi-bin/hgGateway .
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