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

Pawaree Saisawat; Stefan Kohl; Alina C. Hilger; Daw Yang Hwang; Heon Yung Gee; Gabriel C. Dworschak; Velibor Tasic; Tracie Pennimpede; Sivakumar Natarajan; Ethan Sperry; Danilo S. Matassa; Nataša Stajić; Radovan Bogdanovic; Ivo De Blaauw; Carlo L.M. Marcelis; Charlotte H.W. Wijers; Enrika Bartels; Eberhard Schmiedeke; Dominik Schmidt; Stefanie Märzheuser; Sabine Grasshoff-Derr; Stefan Holland-Cunz; Michael Ludwig; Markus M. Nöthen; Markus Draaken; Erwin Brosens; Hugo Heij; Dick Tibboel; Bernhard G. Herrmann; Benjamin D. Solomon; Annelies De Klein; Iris A.L.M. Van Rooij; Franca Esposito; Heiko M. Reutter; Friedhelm Hildebrandt

doi:10.1038/ki.2013.417

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

Pawaree Saisawat, Stefan Kohl, Alina C. Hilger, Daw Yang Hwang, Heon Yung Gee, Gabriel C. Dworschak, Velibor Tasic, Tracie Pennimpede, Sivakumar Natarajan, Ethan Sperry, Danilo S. Matassa, Nataša Stajić, Radovan Bogdanovic, Ivo De Blaauw, Carlo L.M. Marcelis, Charlotte H.W. Wijers, Enrika Bartels, Eberhard Schmiedeke, Dominik Schmidt, Stefanie MärzheuserSabine Grasshoff-Derr, Stefan Holland-Cunz, Michael Ludwig, Markus M. Nöthen, Markus Draaken, Erwin Brosens, Hugo Heij, Dick Tibboel, Bernhard G. Herrmann, Benjamin D. Solomon, Annelies De Klein, Iris A.L.M. Van Rooij, Franca Esposito, Heiko M. Reutter, Friedhelm Hildebrandt

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

93 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1310-1317
Number of pages	8
Journal	Kidney International
Volume	85
Issue number	6
DOIs	https://doi.org/10.1038/ki.2013.417
Publication status	Published - 2014 Jun

Bibliographical note

Funding 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 .

All Science Journal Classification (ASJC) codes

Nephrology

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10.1038/ki.2013.417

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Saisawat, P., Kohl, S., Hilger, A. C., Hwang, D. Y., Yung Gee, H., Dworschak, G. C., Tasic, V., Pennimpede, T., Natarajan, S., Sperry, E., Matassa, D. S., Stajić, N., Bogdanovic, R., De Blaauw, I., Marcelis, C. L. M., Wijers, C. H. W., Bartels, E., Schmiedeke, E., Schmidt, D., ... Hildebrandt, F. (2014). Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney International, 85(6), 1310-1317. https://doi.org/10.1038/ki.2013.417

@article{3591c76f251745dead1060c7cd3bed43,

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.",

author = "Pawaree Saisawat and Stefan Kohl and Hilger, {Alina C.} and Hwang, {Daw Yang} and {Yung Gee}, Heon and Dworschak, {Gabriel C.} and Velibor Tasic and Tracie Pennimpede and Sivakumar Natarajan and Ethan Sperry and Matassa, {Danilo S.} and Nata{\v s}a Staji{\'c} and Radovan Bogdanovic and {De Blaauw}, Ivo and Marcelis, {Carlo L.M.} and Wijers, {Charlotte H.W.} and Enrika Bartels and Eberhard Schmiedeke and Dominik Schmidt and Stefanie M{\"a}rzheuser and Sabine Grasshoff-Derr and Stefan Holland-Cunz and Michael Ludwig and N{\"o}then, {Markus M.} and Markus Draaken and Erwin Brosens and Hugo Heij and Dick Tibboel and Herrmann, {Bernhard G.} and Solomon, {Benjamin D.} and {De Klein}, Annelies and {Van Rooij}, {Iris A.L.M.} and Franca Esposito and Reutter, {Heiko M.} and Friedhelm Hildebrandt",

note = "Funding 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 {\textquoteleft}Network for the Systematic Investigation of the Molecular Causes, Clinical Implications and Psychosocial Outcome of Congenital Uro-Rectal Malformations{\textquoteright} (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 f{\"u}r 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 . ",

year = "2014",

month = jun,

doi = "10.1038/ki.2013.417",

language = "English",

volume = "85",

pages = "1310--1317",

journal = "Kidney International",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "6",

}

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, CLM, Wijers, CHW, 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, IALM, Esposito, F, Reutter, HM & Hildebrandt, F 2014, 'Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association', Kidney International, vol. 85, no. 6, pp. 1310-1317. https://doi.org/10.1038/ki.2013.417

TY - JOUR

T1 - Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

AU - Saisawat, Pawaree

AU - Kohl, Stefan

AU - Hilger, Alina C.

AU - Hwang, Daw Yang

AU - Yung Gee, Heon

AU - Dworschak, Gabriel C.

AU - Tasic, Velibor

AU - Pennimpede, Tracie

AU - Natarajan, Sivakumar

AU - Sperry, Ethan

AU - Matassa, Danilo S.

AU - Stajić, Nataša

AU - Bogdanovic, Radovan

AU - De Blaauw, Ivo

AU - Marcelis, Carlo L.M.

AU - Wijers, Charlotte H.W.

AU - Bartels, Enrika

AU - Schmiedeke, Eberhard

AU - Schmidt, Dominik

AU - Märzheuser, Stefanie

AU - Grasshoff-Derr, Sabine

AU - Holland-Cunz, Stefan

AU - Ludwig, Michael

AU - Nöthen, Markus M.

AU - Draaken, Markus

AU - Brosens, Erwin

AU - Heij, Hugo

AU - Tibboel, Dick

AU - Herrmann, Bernhard G.

AU - Solomon, Benjamin D.

AU - De Klein, Annelies

AU - Van Rooij, Iris A.L.M.

AU - Esposito, Franca

AU - Reutter, Heiko M.

AU - Hildebrandt, Friedhelm

N1 - Funding 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 .

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

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DO - 10.1038/ki.2013.417

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JO - Kidney International

JF - Kidney International

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

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