{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:03:37Z","timestamp":1791216217051,"version":"4.1.0"},"reference-count":63,"publisher":"S. Karger AG","issue":"4","license":[{"start":{"date-parts":[[2013,1,1]],"date-time":"2013-01-01T00:00:00Z","timestamp":1356998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"},{"start":{"date-parts":[[2013,1,1]],"date-time":"2013-01-01T00:00:00Z","timestamp":1356998400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mol Syndromol"],"published-print":{"date-parts":[[2013]]},"abstract":"<jats:p>Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in &lt;i&gt;ENG, ACVRL1 &lt;\/i&gt;or &lt;i&gt;SMAD4&lt;\/i&gt; encoding endothelial cell-expressed proteins involved in TGF-\u03b2 superfamily signalling. The majority of mutations reported on the HHT mutation database are predicted to lead to stop codons, either due to frameshifts or direct nonsense substitutions. The proportion is higher for &lt;i&gt;ENG&lt;\/i&gt; (67%) and &lt;i&gt;SMAD4 &lt;\/i&gt;(65%) than for &lt;i&gt;ACVRL1 &lt;\/i&gt;(42%), p &lt; 0.0001. Here, by focussing on &lt;i&gt;ENG,&lt;\/i&gt; we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating &lt;i&gt;ENG&lt;\/i&gt; mutations, on ExPASy translation, all except one were premature termination codons (PTCs), sited at least 50-55 bp upstream of the final exon-exon boundary of the main endoglin isoform, L-endoglin. This strongly suggests that the mutated RNA species will undergo nonsense-mediated decay. We provide new in vitro expression data to support dominant negative activity of stable truncated endoglin proteins but suggest these will not generate HHT: the single natural stop codon mutation in L-endoglin (sited within 50-55 nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would 8 further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogenesis. Finally, next-generation RNA sequencing data of 7 different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of &lt;i&gt;ENG &lt;\/i&gt;are transcribed. The potential consequences of heterozygous deletions or duplications of such regions are discussed. These data support the haploinsufficiency model for HHT pathogenesis, explain why final exon mutations have not been detected to date in HHT, emphasise the potential need for functional examination of non-PTC-generating mutations, and lead to proposals for an alternate stratification system of mutational types for HHT genotype-phenotype correlations.<\/jats:p>","DOI":"10.1159\/000350208","type":"journal-article","created":{"date-parts":[[2013,4,26]],"date-time":"2013-04-26T14:21:12Z","timestamp":1366986072000},"page":"184-196","source":"Crossref","is-referenced-by-count":16,"title":["Directional Next-Generation RNA Sequencing and Examination of Premature Termination Codon Mutations in Endoglin\/Hereditary Haemorrhagic Telangiectasia"],"prefix":"10.1159","volume":"4","author":[{"given":"F.S.","family":"Govani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Giess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.G.","family":"Mollet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.E.","family":"Begbie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.D.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Game","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.L.","family":"Shovlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2013,4,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.030833"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31450"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31101"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830230943"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90386-8"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2009.181"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1080\/03014469200002112"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20311"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.176552"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20342"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64960-7"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.3.331"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.028712"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002276"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200001000-00008"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10026"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-034124"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.041"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9413"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1998)11:4<286::AID-HUMU6>3.0.CO;2-B"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)15732-2"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33206"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.708818"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(03)00142-7"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.35"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1186\/2040-2384-2-15"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199510053331407"},{"key":"ref28","doi-asserted-by":"publisher","DOI":"10.1038\/37284"},{"key":"ref29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn429"},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-189"},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1068597"},{"key":"ref32","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2796.1999.00398.x"},{"key":"ref33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2005.01555.x"},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2007.11.003"},{"key":"ref35","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600386"},{"key":"ref36","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2131"},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.49.33011"},{"key":"ref38","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.035451"},{"key":"ref39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2009.08.010"},{"key":"ref40","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.5.745"},{"key":"ref41","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.211037"},{"key":"ref42","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01701"},{"key":"ref43","doi-asserted-by":"publisher","DOI":"10.1038\/ng1294-345"},{"key":"ref44","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.10.1983"},{"key":"ref45","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2009.080148"},{"key":"ref46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2008.06.001"},{"key":"ref47","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1080"},{"key":"ref48","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.13.1347"},{"key":"ref49","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-107359"},{"key":"ref50","doi-asserted-by":"publisher","DOI":"10.1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