{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:56:03Z","timestamp":1792079763818,"version":"4.4.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Hirschsprung disease (HSCR) has a higher incidence in children with Down syndrome (DS), which makes trisomy 21 a predisposing factor to HSCR. <jats:italic>DSCAM<\/jats:italic> and <jats:italic>BACE2<\/jats:italic> are close together on the HSCR-associated critical region of chromosome 21. Common variants of <jats:italic>DSCAM<\/jats:italic> and rare variants of <jats:italic>BACE2<\/jats:italic> were implicated to be associated with sporadic HSCR. However, the submucosal neuron defect of DS mouse model could not be rescued by normalization of <jats:italic>Dscam<\/jats:italic>. We aimed to explore the contribution of <jats:italic>DSCAM<\/jats:italic> and <jats:italic>BACE2<\/jats:italic> to the development of the enteric nervous system (ENS) and HSCR susceptibility. We genotyped 133 tag single-nucleotide polymorphisms (SNPs) in <jats:italic>DSCAM<\/jats:italic> and <jats:italic>BACE2<\/jats:italic> gene region in 420 HSCR patients and 1,665 controls of Han Chinese. Expression of <jats:italic>DSCAM<\/jats:italic> and <jats:italic>BACE2<\/jats:italic> homologs was investigated in the developing gut of zebrafish. Overexpression and knockdown of the homologs were performed in zebrafish to investigate their roles in the development of ENS. Two <jats:italic>DSCAM<\/jats:italic> SNPs, rs430255 (<jats:italic>P<\/jats:italic><jats:sub><jats:italic>Addtive<\/jats:italic><\/jats:sub> = 0.0052, <jats:italic>OR<\/jats:italic> = 1.36, 95% CI: 1.10\u20131.68) and rs2837756 (<jats:italic>P<\/jats:italic><jats:sub><jats:italic>Addtive<\/jats:italic><\/jats:sub> = 0.0091, <jats:italic>OR<\/jats:italic> = 1.23, 95% CI: 1.05\u20131.43), showed suggestive association with HSCR risk. Common variants in <jats:italic>BACE2<\/jats:italic> were not associated with HSCR risk. We observed <jats:italic>dscama<\/jats:italic>, <jats:italic>dscamb<\/jats:italic>, and <jats:italic>bace2<\/jats:italic> expression in the developing gut of zebrafish. Knockdown of <jats:italic>dscama<\/jats:italic>, <jats:italic>dscamb<\/jats:italic>, and <jats:italic>bace2<\/jats:italic> caused a reduction of enteric neurons in the hindgut of zebrafish. Overexpression of <jats:italic>DSCAM<\/jats:italic> and <jats:italic>bace2<\/jats:italic> had no effects on neuron number in the hindgut of zebrafish. Our results suggested that common variation of <jats:italic>DSCAM<\/jats:italic> contributed to HSCR risk in Han Chinese. The dysfunction of both <jats:italic>dscams<\/jats:italic> and <jats:italic>bace2<\/jats:italic> caused defects in enteric neuron, indicating that <jats:italic>DSCAM<\/jats:italic> and <jats:italic>BACE2<\/jats:italic> might play functional roles in the occurrence of HSCR. These novel findings might shed new light on the pathogenesis of HSCR.<\/jats:p>","DOI":"10.3389\/fcell.2021.641152","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T08:47:22Z","timestamp":1622450842000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Association Analysis of Variants of DSCAM and BACE2 With Hirschsprung Disease Susceptibility in Han Chinese and Functional Evaluation in Zebrafish"],"prefix":"10.3389","volume":"9","author":[{"given":"Yan-Jiao","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Wen","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Meng","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Xian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-Lei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Rong","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Jie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei-Lin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jmg.2007.053959","article-title":"Hirschsprung disease, associated syndromes and genetics: a review.","volume":"45","author":"Amiel","year":"2008","journal-title":"J. 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