{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T20:03:21Z","timestamp":1781381001373,"version":"3.54.1"},"reference-count":25,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[2003,4]]},"abstract":"<jats:p>\n                  <jats:bold>Background:<\/jats:bold> Hirschsprung\u2019s disease (HSCR) is a congenital disorder characterised by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. Manifestation of the disease has been linked to mutations in genes that encode the crucial signals for the development of the enteric nervous system\u2014the RET and EDNRB signalling pathways. The <jats:italic>Phox2b<\/jats:italic> gene is involved in neurogenesis and regulates <jats:italic>Ret<\/jats:italic> expression in mice, in which disruption of the <jats:italic>Phox2b<\/jats:italic> results in a HSCR-like phenotype.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Aims:<\/jats:bold> To investigate the contribution of <jats:italic>PHOX2B<\/jats:italic> to the HSCR phenotype.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Methods:<\/jats:bold> Using polymerase chain reaction amplification and direct sequencing, we screened <jats:italic>PHOX2B<\/jats:italic> coding regions and intron\/exon boundaries for mutations and polymorphisms in 91 patients with HSCR and 71 ethnically matched controls. Seventy five HSCR patients with no <jats:italic>RET<\/jats:italic> mutations were independently considered. Haplotype and genotype frequencies were compared using the standard case control statistic.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Results:<\/jats:bold> Sequence analysis revealed three new polymorphisms: two novel single nucleotide polymorphisms (A\u2192G<jats:sub>1364<\/jats:sub>; A\u2192C<jats:sub>2607<\/jats:sub>) and a 15 base pair deletion (DEL<jats:sub>2609<\/jats:sub>). Statistically significant differences were found for A\u2192G<jats:sub>1364<\/jats:sub>. Genotypes comprising allele G were underrepresented in patients (19% <jats:italic>v<\/jats:italic> 36%; \u03c7<jats:sup>2<\/jats:sup>=9.30; p<jats:italic>=<\/jats:italic>0.0095 and 22% <jats:italic>v<\/jats:italic> 36%; \u03c7<jats:sup>2<\/jats:sup>=7.38; p<jats:italic>=<\/jats:italic>0.024 for patients with no <jats:italic>RET<\/jats:italic> mutations). Pairwise linkage disequilibrium (LD) analysis revealed no LD between physically close polymorphisms indicating a hot spot for recombination in exon 3.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Conclusion:<\/jats:bold> The <jats:italic>PHOX2B<\/jats:italic> A\u2192G<jats:sub>1364<\/jats:sub> polymorphism is associated with HSCR. Whether it directly contributes to disease susceptibility or represents a marker for a locus in LD with <jats:italic>PHOX2B<\/jats:italic> needs further investigation. Our findings are in accordance with the involvement of <jats:italic>PHOX2B<\/jats:italic> in the signalling pathways governing the development of enteric neurones.<\/jats:p>","DOI":"10.1136\/gut.52.4.563","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T17:42:13Z","timestamp":1047404533000},"page":"563-567","source":"Crossref","is-referenced-by-count":78,"title":["Association study of <i>PHOX2B<\/i> as a candidate gene for Hirschsprung\u2019s disease"],"prefix":"10.1136","volume":"52","author":[{"given":"M","family":"Garcia-Barcel\u00f3","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M H","family":"Sham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V C H","family":"Lui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B L S","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P K H","family":"Tam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2003,4,1]]},"reference":[{"key":"2025090713132638000_52.4.563.1","unstructured":"Holschneider AM. Hirschsprung\u00e2\u0080\u0099s disease. In: Holschneider AM, eds. 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Handbook of human genetic linkage. Baltimore: John Hopkins University Press, 1994."},{"key":"2025090713132638000_52.4.563.21","doi-asserted-by":"publisher","DOI":"10.1038\/326563a0"},{"key":"2025090713132638000_52.4.563.22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/ng868","volume":"31","year":"2002","journal-title":"Nat Genet"},{"key":"2025090713132638000_52.4.563.23","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(200005)15:5<418::AID-HUMU3>3.0.CO;2-2"},{"key":"2025090713132638000_52.4.563.24","doi-asserted-by":"publisher","DOI":"10.1038\/10290"},{"key":"2025090713132638000_52.4.563.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001-109"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gut.52.4.563","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T20:14:02Z","timestamp":1757276042000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gut.52.4.563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,4]]},"references-count":25,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2003,4,1]]},"published-print":{"date-parts":[[2003,4]]}},"alternative-id":["10.1136\/gut.52.4.563"],"URL":"https:\/\/doi.org\/10.1136\/gut.52.4.563","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,4]]}}}