TY - JOUR
T1 - Hereditary hemorrhagic telangiectasia
T2 - Breakpoint characterization of a novel large deletion in ACVRL1 suggests the causing mechanism
AU - Boeri, Laura
AU - Radi, Orietta
AU - Canzonieri, Cecilia
AU - Buscarini, Elisabetta
AU - Scatigno, Agnese
AU - Minelli, Antonella
AU - Ornati, Federica
AU - Pagella, Fabio
AU - Danesino, Cesare
AU - Olivieri, Carla
PY - 2013/3
Y1 - 2013/3
N2 - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10% are large deletions and duplications. Here we present a large novel deletion in ACVRL1 gene and its molecular characterization in a 3 generation Italian family. We employed short tandem repeats (STRs) analysis, direct sequencing, multiplex ligation-dependant probe amplification (MLPA) analysis, and 'deletion-specific' PCR methods. STRs Analysis at ENG and ACVRL1 loci suggested a positive linkage for ACVRL1. Direct sequencing of this gene did not identify any mutations, while MLPA identified a large deletion. These results were confirmed and exactly characterized with a 'deletion-specific' PCR: the deletion size is 4,594 bp and breakpoints in exon 3 and intron 8 show the presence of short direct repeats of 7 bp [GCCCCAC]. We hypothesize, as causative molecular mechanism, the replication slippage model. Understanding the fine mechanisms associated with genomic rearrangements may indicate the nonrandomness of these events, highlighting hot spots regions. The complete concordance among MLPA, STRs analysis and 'deletion-specific PCR' supports the usefulness of MLPA in HHT molecular analysis.
AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10% are large deletions and duplications. Here we present a large novel deletion in ACVRL1 gene and its molecular characterization in a 3 generation Italian family. We employed short tandem repeats (STRs) analysis, direct sequencing, multiplex ligation-dependant probe amplification (MLPA) analysis, and 'deletion-specific' PCR methods. STRs Analysis at ENG and ACVRL1 loci suggested a positive linkage for ACVRL1. Direct sequencing of this gene did not identify any mutations, while MLPA identified a large deletion. These results were confirmed and exactly characterized with a 'deletion-specific' PCR: the deletion size is 4,594 bp and breakpoints in exon 3 and intron 8 show the presence of short direct repeats of 7 bp [GCCCCAC]. We hypothesize, as causative molecular mechanism, the replication slippage model. Understanding the fine mechanisms associated with genomic rearrangements may indicate the nonrandomness of these events, highlighting hot spots regions. The complete concordance among MLPA, STRs analysis and 'deletion-specific PCR' supports the usefulness of MLPA in HHT molecular analysis.
KW - ACVRL1
KW - Large deletion
KW - MLPA
KW - Short direct repeats
KW - Slippage
UR - http://www.scopus.com/inward/record.url?scp=84876256915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876256915&partnerID=8YFLogxK
U2 - 10.1159/000347029
DO - 10.1159/000347029
M3 - Article
C2 - 23653583
AN - SCOPUS:84876256915
VL - 4
SP - 119
EP - 124
JO - Molecular Syndromology
JF - Molecular Syndromology
SN - 1661-8769
IS - 3
ER -