Imperial College London

Professor Claire Shovlin

Faculty of MedicineNational Heart & Lung Institute

Professor of Practice (Clinical and Molecular Medicine)



c.shovlin Website




534Block L Hammersmith HospitalHammersmith Campus






BibTex format

author = {Govani, FS and Giess, A and Mollet, IG and Begbie, ME and Jones, MD and Game, L and Shovlin, CL},
doi = {10.1159/000350208},
journal = {Molecular Syndromology},
pages = {184--196},
title = {Directional Next-Generation RNA Sequencing and Examination of Premature Termination Codon Mutations in Endoglin/Hereditary Haemorrhagic Telangiectasia},
url = {},
volume = {4},
year = {2013}

RIS format (EndNote, RefMan)

AB - Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in ENG, ACVRL1 or SMAD4 encoding endothelial cell-expressed proteins involved in TGF- 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 ENG (67%) and SMAD4 (65%) than for ACVRL1 (42%), p<0.0001). Here, by focussing on ENG, we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating ENG mutations, on ExPASy translation, all except one was a premature termination codon, sited at least 50-55bp 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 50-55nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would eight further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogeneses. Finally, next generation RNA sequencing data of seven different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of ENG 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
AU - Govani,FS
AU - Giess,A
AU - Mollet,IG
AU - Begbie,ME
AU - Jones,MD
AU - Game,L
AU - Shovlin,CL
DO - 10.1159/000350208
EP - 196
PY - 2013///
SN - 1661-8777
SP - 184
TI - Directional Next-Generation RNA Sequencing and Examination of Premature Termination Codon Mutations in Endoglin/Hereditary Haemorrhagic Telangiectasia
T2 - Molecular Syndromology
UR -
UR -
VL - 4
ER -