Phenotype Variation in Two-Locus Mouse Models of Hirschsprung Disease: Tissue-Specific Interaction between Ret and Ednrb
Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2003-02, Vol.100 (4), p.1826-1831 |
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| creator | McCallion, Andrew S. Stames, Erine Conlon, Ronald A. Chakravarti, Aravinda |
| description | Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development. |
| doi_str_mv | 10.1073/pnas.0337540100 |
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Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0337540100</identifier><identifier>PMID: 12574515</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Alleles ; Animals ; Biological Sciences ; Disease ; Disease Models, Animal ; Drosophila Proteins ; Female ; Ganglia ; Gender bias ; Genetic mutation ; Genotypes ; Heterozygote ; Hirschsprung Disease - genetics ; Hirschsprung Disease - physiopathology ; Human genetics ; Kidney - embryology ; Male ; Medical genetics ; Mice ; Mutation ; Nervous system diseases ; Penetrance ; Phenotype ; Phenotypes ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-ret ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Receptor, Endothelin B ; Receptors, Endothelin - genetics ; Receptors, Endothelin - metabolism ; Rodents ; Sex Factors ; Signal Transduction</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-02, Vol.100 (4), p.1826-1831</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Feb 18, 2003</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c522t-31a811a445f0e90498d887fb494fb143890512990cab270fccf0c078d140ee323</citedby><cites>FETCH-LOGICAL-c522t-31a811a445f0e90498d887fb494fb143890512990cab270fccf0c078d140ee323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/4.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3138444$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3138444$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12574515$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McCallion, Andrew S.</creatorcontrib><creatorcontrib>Stames, Erine</creatorcontrib><creatorcontrib>Conlon, Ronald A.</creatorcontrib><creatorcontrib>Chakravarti, Aravinda</creatorcontrib><title>Phenotype Variation in Two-Locus Mouse Models of Hirschsprung Disease: Tissue-Specific Interaction between Ret and Ednrb</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development.</description><subject>Alleles</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Drosophila Proteins</subject><subject>Female</subject><subject>Ganglia</subject><subject>Gender bias</subject><subject>Genetic mutation</subject><subject>Genotypes</subject><subject>Heterozygote</subject><subject>Hirschsprung Disease - genetics</subject><subject>Hirschsprung Disease - physiopathology</subject><subject>Human genetics</subject><subject>Kidney - embryology</subject><subject>Male</subject><subject>Medical genetics</subject><subject>Mice</subject><subject>Mutation</subject><subject>Nervous system diseases</subject><subject>Penetrance</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-ret</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Receptor, Endothelin B</subject><subject>Receptors, Endothelin - genetics</subject><subject>Receptors, Endothelin - metabolism</subject><subject>Rodents</subject><subject>Sex Factors</subject><subject>Signal Transduction</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1v1DAQxSMEokvhzAUhiwOc0o4_srGROKBSaKUiECxcLceZdL3K2sF2aPvfk2VX3YKQuMwc5veeZuYVxVMKRxRqfjx4k46A87oSQAHuFTMKipZzoeB-MQNgdSkFEwfFo5RWAKAqCQ-LA8qqWlS0mhXXn5foQ74ZkHw30ZnsgifOk8VVKC-CHRP5GMaEU22xTyR05MzFZJdpiKO_JO9cQpPwNVm4lEYsvw5oXecsOfcZo7G_7RrMV4iefMFMjG_Jaetj87h40Jk-4ZNdPyy-vT9dnJyVF58-nJ-8vShtxVguOTWSUiNE1QEqEEq2UtZdI5ToGiq4VFBRphRY07AaOms7sFDLlgpA5IwfFm-2vsPYrLG16HM0vR6iW5t4o4Nx-s-Jd0t9GX5qKpSictK_3Olj-DFiynrtksW-Nx6nz-iag-Cihv-CVM4VZzWdwBd_gaswRj89QTOgnAk-30DHW8jGkFLE7nZjCnoTvd5Er_fRT4rndw_d87usJ-DVDtgo93agxbQcm-tu7PuM1_mO1b_JCXi2BVYph3hLcMqlEIL_AlWCy-0</recordid><startdate>20030218</startdate><enddate>20030218</enddate><creator>McCallion, Andrew S.</creator><creator>Stames, Erine</creator><creator>Conlon, Ronald A.</creator><creator>Chakravarti, Aravinda</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><general>The National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20030218</creationdate><title>Phenotype Variation in Two-Locus Mouse Models of Hirschsprung Disease: Tissue-Specific Interaction between Ret and Ednrb</title><author>McCallion, Andrew S. ; 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Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12574515</pmid><doi>10.1073/pnas.0337540100</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alleles Animals Biological Sciences Disease Disease Models, Animal Drosophila Proteins Female Ganglia Gender bias Genetic mutation Genotypes Heterozygote Hirschsprung Disease - genetics Hirschsprung Disease - physiopathology Human genetics Kidney - embryology Male Medical genetics Mice Mutation Nervous system diseases Penetrance Phenotype Phenotypes Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-ret Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Receptor, Endothelin B Receptors, Endothelin - genetics Receptors, Endothelin - metabolism Rodents Sex Factors Signal Transduction |
| title | Phenotype Variation in Two-Locus Mouse Models of Hirschsprung Disease: Tissue-Specific Interaction between Ret and Ednrb |
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