| pubmed-article:19360096 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C0035820 | lld:lifeskim |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C0034792 | lld:lifeskim |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C0312418 | lld:lifeskim |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C0036667 | lld:lifeskim |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C1711207 | lld:lifeskim |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C2606910 | lld:lifeskim |
| pubmed-article:19360096 | lifeskim:mentions | umls-concept:C0321230 | lld:lifeskim |
| pubmed-article:19360096 | pubmed:issue | 4 | lld:pubmed |
| pubmed-article:19360096 | pubmed:dateCreated | 2009-4-10 | lld:pubmed |
| pubmed-article:19360096 | pubmed:abstractText | Gastro-intestinal nematodes in ruminants, especially Haemonchus contortus, are a global threat to sheep and cattle farming. The emergence of drug resistance, and even multi-drug resistance to the currently available classes of broad spectrum anthelmintics, further stresses the need for new drugs active against gastro-intestinal nematodes. A novel chemical class of synthetic anthelmintics, the Amino-Acetonitrile Derivatives (AADs), was recently discovered and the drug candidate AAD-1566 (monepantel) was chosen for further development. Studies with Caenorhabditis elegans suggested that the AADs act via nicotinic acetylcholine receptors (nAChR) of the nematode-specific DEG-3 subfamily. Here we identify nAChR genes of the DEG-3 subfamily from H. contortus and investigate their role in AAD sensitivity. Using a novel in vitro selection procedure, mutant H. contortus populations of reduced sensitivity to AAD-1566 were obtained. Sequencing of full-length nAChR coding sequences from AAD-susceptible H. contortus and their AAD-1566-mutant progeny revealed 2 genes to be affected. In the gene monepantel-1 (Hco-mptl-1, formerly named Hc-acr-23H), a panel of mutations was observed exclusively in the AAD-mutant nematodes, including deletions at intron-exon boundaries that result in mis-spliced transcripts and premature stop codons. In the gene Hco-des-2H, the same 135 bp insertion in the 5' UTR created additional, out of frame start codons in 2 independent H. contortus AAD-mutants. Furthermore, the AAD mutants exhibited altered expression levels of the DEG-3 subfamily nAChR genes Hco-mptl-1, Hco-des-2H and Hco-deg-3H as quantified by real-time PCR. These results indicate that Hco-MPTL-1 and other nAChR subunits of the DEG-3 subfamily constitute a target for AAD action against H. contortus and that loss-of-function mutations in the corresponding genes may reduce the sensitivity to AADs. | lld:pubmed |
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| pubmed-article:19360096 | pubmed:language | eng | lld:pubmed |
| pubmed-article:19360096 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19360096 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:19360096 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:19360096 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:19360096 | pubmed:month | Apr | lld:pubmed |
| pubmed-article:19360096 | pubmed:issn | 1553-7374 | lld:pubmed |
| pubmed-article:19360096 | pubmed:author | pubmed-author:RoditiIsabelI | lld:pubmed |
| pubmed-article:19360096 | pubmed:author | pubmed-author:KaminskyRonal... | lld:pubmed |
| pubmed-article:19360096 | pubmed:author | pubmed-author:MäserPascalP | lld:pubmed |
| pubmed-article:19360096 | pubmed:author | pubmed-author:RufenerLucien... | lld:pubmed |
| pubmed-article:19360096 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:19360096 | pubmed:volume | 5 | lld:pubmed |
| pubmed-article:19360096 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:19360096 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:19360096 | pubmed:pagination | e1000380 | lld:pubmed |
| pubmed-article:19360096 | pubmed:dateRevised | 2009-11-18 | lld:pubmed |
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| pubmed-article:19360096 | pubmed:year | 2009 | lld:pubmed |
| pubmed-article:19360096 | pubmed:articleTitle | Haemonchus contortus acetylcholine receptors of the DEG-3 subfamily and their role in sensitivity to monepantel. | lld:pubmed |
| pubmed-article:19360096 | pubmed:affiliation | Novartis Centre de Recherche Santé Animale, St Aubin (FR), Switzerland. | lld:pubmed |
| pubmed-article:19360096 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:19360096 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| http://linkedlifedata.com/r... | pubmed:referesTo | pubmed-article:19360096 | lld:pubmed |
