Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia
Renal hypodysplasia (RHD) is characterized by small and/or disorganized kidneys following abnormal organogenesis. Mutations in several genes have been identified recently to be associated with RHD in humans, including BMP4, a member of the transforming growth factor (TGF)-β family of growth factors....
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| Veröffentlicht in: | Nephrology, dialysis, transplantation dialysis, transplantation, 2013-01, Vol.28 (1), p.227-232 |
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| creator | Schild, Raphael Knüppel, Tanja Konrad, Martin Bergmann, Carsten Trautmann, Agnes Kemper, Markus J Wu, Kongming Yaklichkin, Sergey Wang, Jing Pestell, Richard Müller-Wiefel, Dirk E Schaefer, Franz Weber, Stefanie |
| description | Renal hypodysplasia (RHD) is characterized by small and/or disorganized kidneys following abnormal organogenesis. Mutations in several genes have been identified recently to be associated with RHD in humans, including BMP4, a member of the transforming growth factor (TGF)-β family of growth factors. DACH1 has been proposed as a candidate gene for RHD because of its involvement in the EYA-SIX-DACH network of renal developmental genes. Here, we present a patient with renal dysplasia carrying homozygous missense mutations in both BMP4 (p.N150K) and DACH1 (p.R684C). The genotype-phenotype correlation in the family hints at an oligogenic mode of inheritance of the disease in this kindred. Functional analyses of the identified DACH1 mutation in HEK293T cells demonstrated enhanced suppression of the TGF-β pathway suggesting that both mutations could act synergistically in the development of the phenotype in this patient. This finding provides a model for RHD as an oligo-/polygenic disorder and supports a role for DACH1 in the development of RHD in humans. |
| doi_str_mv | 10.1093/ndt/gfs539 |
| format | Article |
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Mutations in several genes have been identified recently to be associated with RHD in humans, including BMP4, a member of the transforming growth factor (TGF)-β family of growth factors. DACH1 has been proposed as a candidate gene for RHD because of its involvement in the EYA-SIX-DACH network of renal developmental genes. Here, we present a patient with renal dysplasia carrying homozygous missense mutations in both BMP4 (p.N150K) and DACH1 (p.R684C). The genotype-phenotype correlation in the family hints at an oligogenic mode of inheritance of the disease in this kindred. Functional analyses of the identified DACH1 mutation in HEK293T cells demonstrated enhanced suppression of the TGF-β pathway suggesting that both mutations could act synergistically in the development of the phenotype in this patient. This finding provides a model for RHD as an oligo-/polygenic disorder and supports a role for DACH1 in the development of RHD in humans.</description><identifier>ISSN: 0931-0509</identifier><identifier>EISSN: 1460-2385</identifier><identifier>DOI: 10.1093/ndt/gfs539</identifier><identifier>PMID: 23262432</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adult ; Bone Morphogenetic Protein 4 - genetics ; Exceptional Cases ; Eye Proteins - genetics ; Genetic Association Studies ; Homozygote ; Humans ; Kidney - abnormalities ; Male ; Mutation, Missense ; Polycystic Kidney, Autosomal Recessive - genetics ; Transcription Factors - genetics ; Urogenital Abnormalities - genetics ; Young Adult</subject><ispartof>Nephrology, dialysis, transplantation, 2013-01, Vol.28 (1), p.227-232</ispartof><rights>The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 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Mutations in several genes have been identified recently to be associated with RHD in humans, including BMP4, a member of the transforming growth factor (TGF)-β family of growth factors. DACH1 has been proposed as a candidate gene for RHD because of its involvement in the EYA-SIX-DACH network of renal developmental genes. Here, we present a patient with renal dysplasia carrying homozygous missense mutations in both BMP4 (p.N150K) and DACH1 (p.R684C). The genotype-phenotype correlation in the family hints at an oligogenic mode of inheritance of the disease in this kindred. Functional analyses of the identified DACH1 mutation in HEK293T cells demonstrated enhanced suppression of the TGF-β pathway suggesting that both mutations could act synergistically in the development of the phenotype in this patient. This finding provides a model for RHD as an oligo-/polygenic disorder and supports a role for DACH1 in the development of RHD in humans.</description><subject>Adult</subject><subject>Bone Morphogenetic Protein 4 - genetics</subject><subject>Exceptional Cases</subject><subject>Eye Proteins - genetics</subject><subject>Genetic Association Studies</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Kidney - abnormalities</subject><subject>Male</subject><subject>Mutation, Missense</subject><subject>Polycystic Kidney, Autosomal Recessive - genetics</subject><subject>Transcription Factors - genetics</subject><subject>Urogenital Abnormalities - genetics</subject><subject>Young Adult</subject><issn>0931-0509</issn><issn>1460-2385</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LAzEUDKLYWr34AyRHEdbmo_t1EbR-VFD0oOeQzb60kd2kbrJK_fWmtIqeHu_NMG-YQeiYknNKSj62dRjPtU95uYOGdJKRhPEi3UXDCNKEpKQcoAPv3wghJcvzfTRgnGVswtkQmWvXVw3ghWvd12rueo9b4z1YD7jtgwzGWY-NxdeX0xnF0tb46vF5sr5IvIww2IA_TVjgyjQyQCcbrFY-GIU7sHGpV37ZSG_kIdrTsvFwtJ0j9Hp78zKdJQ9Pd_fTy4dE8bwIiQZGKkozAsCp4hJAS5blClRRa1bpQhIKtGAKaiCMAqu1BJVqXQKDKtV8hC42usu-aqFW0WA0JZadaWW3Ek4a8R-xZiHm7kPwjGZ5RqPA6Vagc-89-CBiIgqaRlqI-QjKcs5TTso8Us82VNU57zvQv28oEetuROxGbLqJ5JO_xn6pP2Xwb9r1jxo</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Schild, Raphael</creator><creator>Knüppel, Tanja</creator><creator>Konrad, Martin</creator><creator>Bergmann, Carsten</creator><creator>Trautmann, Agnes</creator><creator>Kemper, Markus J</creator><creator>Wu, Kongming</creator><creator>Yaklichkin, Sergey</creator><creator>Wang, Jing</creator><creator>Pestell, Richard</creator><creator>Müller-Wiefel, Dirk E</creator><creator>Schaefer, Franz</creator><creator>Weber, Stefanie</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130101</creationdate><title>Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia</title><author>Schild, Raphael ; Knüppel, Tanja ; Konrad, Martin ; Bergmann, Carsten ; Trautmann, Agnes ; Kemper, Markus J ; Wu, Kongming ; Yaklichkin, Sergey ; Wang, Jing ; Pestell, Richard ; Müller-Wiefel, Dirk E ; Schaefer, Franz ; Weber, Stefanie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-fe20b1160ee31c3aeefa267cec8df2bf8a01e182cede021e2dfaec5ff9e2eb5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Bone Morphogenetic Protein 4 - genetics</topic><topic>Exceptional Cases</topic><topic>Eye Proteins - genetics</topic><topic>Genetic Association Studies</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Kidney - abnormalities</topic><topic>Male</topic><topic>Mutation, Missense</topic><topic>Polycystic Kidney, Autosomal Recessive - genetics</topic><topic>Transcription Factors - genetics</topic><topic>Urogenital Abnormalities - genetics</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schild, Raphael</creatorcontrib><creatorcontrib>Knüppel, Tanja</creatorcontrib><creatorcontrib>Konrad, Martin</creatorcontrib><creatorcontrib>Bergmann, Carsten</creatorcontrib><creatorcontrib>Trautmann, Agnes</creatorcontrib><creatorcontrib>Kemper, Markus J</creatorcontrib><creatorcontrib>Wu, Kongming</creatorcontrib><creatorcontrib>Yaklichkin, Sergey</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Pestell, Richard</creatorcontrib><creatorcontrib>Müller-Wiefel, Dirk E</creatorcontrib><creatorcontrib>Schaefer, Franz</creatorcontrib><creatorcontrib>Weber, Stefanie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nephrology, dialysis, transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schild, Raphael</au><au>Knüppel, Tanja</au><au>Konrad, Martin</au><au>Bergmann, Carsten</au><au>Trautmann, Agnes</au><au>Kemper, Markus J</au><au>Wu, Kongming</au><au>Yaklichkin, Sergey</au><au>Wang, Jing</au><au>Pestell, Richard</au><au>Müller-Wiefel, Dirk E</au><au>Schaefer, Franz</au><au>Weber, Stefanie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia</atitle><jtitle>Nephrology, dialysis, transplantation</jtitle><addtitle>Nephrol Dial Transplant</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>28</volume><issue>1</issue><spage>227</spage><epage>232</epage><pages>227-232</pages><issn>0931-0509</issn><eissn>1460-2385</eissn><abstract>Renal hypodysplasia (RHD) is characterized by small and/or disorganized kidneys following abnormal organogenesis. Mutations in several genes have been identified recently to be associated with RHD in humans, including BMP4, a member of the transforming growth factor (TGF)-β family of growth factors. DACH1 has been proposed as a candidate gene for RHD because of its involvement in the EYA-SIX-DACH network of renal developmental genes. Here, we present a patient with renal dysplasia carrying homozygous missense mutations in both BMP4 (p.N150K) and DACH1 (p.R684C). The genotype-phenotype correlation in the family hints at an oligogenic mode of inheritance of the disease in this kindred. Functional analyses of the identified DACH1 mutation in HEK293T cells demonstrated enhanced suppression of the TGF-β pathway suggesting that both mutations could act synergistically in the development of the phenotype in this patient. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Adult Bone Morphogenetic Protein 4 - genetics Exceptional Cases Eye Proteins - genetics Genetic Association Studies Homozygote Humans Kidney - abnormalities Male Mutation, Missense Polycystic Kidney, Autosomal Recessive - genetics Transcription Factors - genetics Urogenital Abnormalities - genetics Young Adult |
| title | Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia |
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