{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T04:30:00Z","timestamp":1793766600200,"version":"4.6.1"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,2,18]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>Ednrb<\/jats:italic>\n                    in the context of\n                    <jats:italic>Ret<\/jats:italic>\n                    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\n                    <jats:italic>Ednrb<\/jats:italic>\n                    in the presence of half the genetic dose of\n                    <jats:italic>Ret<\/jats:italic>\n                    determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at\n                    <jats:italic>Ednrb<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0337540100","type":"journal-article","created":{"date-parts":[[2003,2,18]],"date-time":"2003-02-18T15:04:50Z","timestamp":1045580690000},"page":"1826-1831","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":142,"title":["Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between\n                    <i>Ret<\/i>\n                    and\n                    <i>Ednrb<\/i>"],"prefix":"10.1073","volume":"100","author":[{"given":"Andrew S.","family":"McCallion","sequence":"first","affiliation":[{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Genetics, Case Western Reserve University, Cleveland, OH 44106-4955"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erine","family":"Stames","sequence":"additional","affiliation":[{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Genetics, Case Western Reserve University, Cleveland, OH 44106-4955"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A.","family":"Conlon","sequence":"additional","affiliation":[{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Genetics, Case Western Reserve University, Cleveland, OH 44106-4955"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravinda","family":"Chakravarti","sequence":"additional","affiliation":[{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Genetics, Case Western Reserve University, Cleveland, OH 44106-4955"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2003,2,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/5.3.355"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/324342"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1159\/000484771"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.14.1503"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/367378a0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0496-442"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.9.1449"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/302184"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01194795"},{"key":"e_1_3_3_10_2","first-page":"358","volume":"317","author":"Lyonnet S","year":"1994","unstructured":"S Lyonnet, P Edery, L M Mulligan, A Pelet, E Dow, L Abel, S Holder, C Nihoul-Fekete, B A Ponder, A Munnich C R Acad Sci III 317, 358\u2013362 (1994).","journal-title":"C R Acad Sci III"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.9.3.215"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0298-171"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/86860"},{"key":"e_1_3_3_14_2","first-page":"568","volume":"46","author":"Badner J A","year":"1990","unstructured":"J A Badner, W K Sieber, K L Garver, A Chakravarti Am J Hum Genet 46, 568\u2013580 (1990).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_15_2","volume-title":"The Metabolic and Molecular Basis of Inherited Disease","author":"Chakravarti A","year":"2000","unstructured":"A Chakravarti, S Lyonnet The Metabolic and Molecular Basis of Inherited Disease, eds C R Scriver, W S Sly, D Valle, A L Beaudet (McGraw\u2013Hill, New York, , Chap. 251. (2000)."},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90018-3"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90017-5"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/367380a0"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.11.2089"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.2.867"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003359900790"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003359900754"},{"key":"e_1_3_3_23_2","first-page":"267","volume":"108","author":"Stockhofe-Zurwieden N","year":"2001","unstructured":"N Stockhofe-Zurwieden, R M Buijs, M De Jong Dtsch Tierarztl Wochenschr 108, 267\u2013269 (2001).","journal-title":"Dtsch Tierarztl Wochenschr"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/367377a0"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90016-7"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0749.2001.140305.x"},{"key":"e_1_3_3_27_2","volume-title":"The Third International Meeting: Hirschsprung Disease and Related Neurocristophathies","author":"Torfs C","year":"1998","unstructured":"C Torfs The Third International Meeting: Hirschsprung Disease and Related Neurocristophathies (Evian, France, 1998)."},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng998"},{"key":"e_1_3_3_29_2","first-page":"14","volume":"38","author":"Bielschowsky M","year":"1960","unstructured":"M Bielschowsky, G C Schofield Proc Univ Ortag Med Sch 38, 14\u201315 (1960).","journal-title":"Proc Univ Ortag Med Sch"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jhered.a107457"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.20.3963"},{"key":"e_1_3_3_32_2","first-page":"17","volume":"10","author":"Rhim H","year":"2000","unstructured":"H Rhim, K J Dunn, A Aronzon, S Mac, M Cheng, M L Lamoreux, S M Tilghman, W J Pavan Genome Res 10, 17\u201329 (2000).","journal-title":"Genome Res"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(93)25025-W"},{"key":"e_1_3_3_34_2","volume-title":"Inborn Errors of Development","author":"McCallion A S","year":"2002","unstructured":"A S McCallion, A Chakravarti Inborn Errors of Development (Oxford Univ. Press, San Francisco, 2002)."},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204918"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/382076a0"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/382073a0"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/382070a0"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.122.6.1919"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI524"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1086\/302329"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050797"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.268"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng868"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1056072"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/97.3-4.639"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.5.1806"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0337540100","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T21:38:41Z","timestamp":1650922721000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0337540100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,2,6]]},"references-count":47,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2003,2,18]]}},"alternative-id":["10.1073\/pnas.0337540100"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0337540100","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,2,6]]},"assertion":[{"value":"2002-08-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2002-12-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2003-02-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}