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Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia
Author(s) -
Cymerman Urszula,
Vera Sonia,
Karabegovic Amna,
Abdalla Salma,
Letarte Michelle
Publication year - 2003
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10203
Subject(s) - exon , biology , genetics , microbiology and biotechnology , splice site mutation , missense mutation , telangiectases , multiplex ligation dependent probe amplification , mutation , frameshift mutation , nonsense mutation , exon skipping , splice , mutant , exon trapping , gene , alternative splicing , telangiectasia , medicine , surgery
Abstract Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular dysplasia caused by mutations in the endoglin ( ENG ) gene and associated with epistaxis, telangiectases, and a high incidence of pulmonary arteriovenous malformations. To efficiently detect deletions and insertions, we optimized a quantitative multiplex polymerase chain reaction (QMPCR) analysis. We report 17 novel mutations, of which six were detected by QMPCR. Three deletions occurring in intronic sequences were associated with a single copy of exons 9a–14, exon 5, and exons 7–8, respectively. A transient 70kDa monomeric mutant protein resulted from the in‐frame deletion of exons 7 and 8 but no mutant protein was present in the other cases. Deletion (in exon 10) or insertion (in exon 7) of two nucleotides, as well as a 1‐bp deletion in the small exon 9a were found by QMPCR. Sequencing was required to detect single nucleotide deletions/insertions in exons 2, 5, 6, and 8. No mutant proteins were associated with these frame shift mutations. Two novel splice site mutations resulted in skipping of exons 2 and 4, respectively, while a previously reported intron 3 splice mutant was observed as a de novo mutation. We also report five novel nonsense and missense mutations, including one de novo. Review of the 80 HHT1 families reported to date indicates that 10% would not be resolved by sequencing and that an additional 25% could be revealed by QMPCR performed prior to sequencing. Thus the use of QMPCR accelerates genetic screening for HHT1 and resolves mutations affecting whole exons. Hum Mutat 21:482–492, 2003. © 2003 Wiley‐Liss, Inc.