Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients

Abstract

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber disease is a systemic fibrovascular dysplasia with an autosomal dominant inheritance pattern. Mutations in two genes, endoglin and ALK-1, are known to cause HHT, both of which mediate signaling by transforming growth factor b ligands in vascular endothelial cells. Ten patients were analyzed. Diagnosis of HHT was carried out by means of family history, recurrent bleeding, and the presence of multiple telangiectases lesions. Conformation-sensitive gel electrophoresis analyses with consistent abnormal migration patterns were cloned and sequenced using the MegaBace 1000 DNA automated analyzer. Three novel mutations were identified in the coding sequence of the ALK-1 gene in five patients and their families, which demonstrated clinical manifestations of HHT type 2. These mutations included a G insertion and a T deletion of single base pairs in exons 3 and 7, as well as missense mutations in exons 7 and 8 of the ALK-1 gene. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2.Keywords Activin receptor-like kinase 1 (ALK1) Á Endoglin (ENG) Á Hereditary hemorrhagic telangiectasia (HHT)

Spectrum of Novel Hereditary Hemorrhagic Telangiectasia Variants in an Austrian Patient Cohort

“…The index patient had pancreatic and hepatic arteriovenous malformations. Two other known variants found in two other families are the missense transition c.1204G>A (p.Gly402Ser; SCV000346043) [10,26] in exon 8 in a highly conserved residue (Supplementary Fig. 4) and the c.1435C>T (p.Arg479X; SCV000346044) nonsense transition in exon 10 (Supplementary Fig.…”

Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

“…[31] c.773-2A > C Splice Site p.? [19] c.778A > C Missense p.Ile260Leu [24] c.793A > C Missense p.Thr265Pro [37] c.811_823del13bp Deletion p.Thr271Serfs*26 [35] c.818T > C Missense p.Leu273Pro [48] c.821_824dupGGCT Duplication p.Ile276Alafs*117 [40] c.822G > A Missense p.Trp274* [45] c.827T > C Missense p.Ile276Thr [48] c.835_837dupTAC Duplication p.Tyr279dup [14] c.838C > G Missense p.His280Asp [25] c.839A > G Missense p.His280Arg [45] c.842delA Deletion p.Glu281Glyfs*20 [26] c.851C > T Missense p.Ser284Phe [48] c.853dupC Duplication p.Leu285Profs*107 [20] c.853C > T Missense p.Leu285Phe [31] c.854T > C Missense p.Leu285Pro [58] c.858C > G Missense p.Tyr286* [25] c.858C > A Missense p.Tyr286* [35] c.863_909del47 Deletion p.Phe288Cysfs*88 [14] c.864dupT Duplication p.Leu289Serfs*103 [38] Continued c.866T > C Missense p.Leu289Pro [24] c.870delG Deletion p.Arg219Aspfs*10 [14] c.874delC Deletion p.Gln292Argfs*9 [30] c.874C > T Missense p.Gln292* [19] c.875A > C Missense p.Gln292Pro [26] c.881T > G Missense p.Leu294Arg [45] c.905T > G Missense p.Leu302Arg [26] c.913T > C Missense p.Ser305Pro [48] c.913delT Deletion p.Ser305Profs*49 [59] c.914C > T Missense p.Ser305Phe [17] c.916G > C Missense p.Ala306Pro [31] c.917C > A Missense p.Ala306Glu [30] c.921_927dupATGCGGC Duplication p.Leu310Metfs*84 [47] c.924C > A Missense p.Cys308* [38] c.925G > T Missense p.Gly309Cys ...…”

Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia from two different regions of Brazil

“…In addition, for patients from center 2 that could not be reached by the investigators (due to death or loss of follow-up), data from the medical records were included after a waiver for written informed consent was obtained from the institution IRB. The waiver also included the reanalysis of stored DNA samples collected for the same purpose as part of a previous study in our institution (ASSIS et al, 2007).…”