Mutations in endoglin and in activin receptor‐like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is a rare disorder with one per 6000-10,000 affected individuals in the general Caucasian population. HHT is genetically heterogeneous, involving at least two loci HHT1 mapping to chromosome 9q34.1 and HHT2 mapping to chromosome 12q31. The loci have been identified as endoglin (ENG) and activin receptor-like kinase 1 (ALK1). In order to gain knowledge of the genotype distribution and prevalence in the Danish population and to establish a reproducible and sensitive molecular genetic test method, we developed a denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci. Twenty-five Danish HHT families were tested. A total of eight new as well as seven previously reported mutations were identified. A founder mutation was characterized present in seven families and possibly introduced around 350 years ago. In one individual, a presumed spontaneous mutation was characterized. The method developed proved to be very sensitive for mutation detection in both ENG and ALK1. Genetic screening in HHT families facilitates an early treatment strategy for silent HHT manifestations in first degree relatives.

DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population

“…Ten different mutations, all consisting in 1-bp substitutions, were undetectable by SSCP analysis. This suggests that DHPLC is particularly suitable for detecting ALK1 mutations, since 1-bp substitutions account for 89 of the 131 ALK1 mutations reported thus far (Bayrak-Toydemir et al, 2004;Brusgaard et al, 2004;Letteboer et al, 2005;Abdalla et al, 2005;Kuehl et al, 2005;Schulte et al, 2005). The detection rate for transitions and transversions were similar with the two methods.…”

“…The existence of a third locus has been reported (Cole et al, 2005). Thus far, 163 mutations of the ENG gene and 131 mutations of the ALK1 gene, mainly detected with direct sequencing, have been described (Bayrak-Toydemir et al, 2004;Brusgaard et al, 2004;Letteboer et al, 2005;Abdalla et al, 2005;Kuehl et al, 2005;Schulte et al, 2005) and, with few exceptions, the mutations tend to be family-specific.…”

Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

“…[21] c.65delA Deletion p.Asp22Alafs*3 [14] c.69delT Deletion p.Val24* [14] c.74_78delAGCCGins176bp Delins p.? [19] c.81dupT Duplication p.Arg28Serfs*10 [22] c.86delG Deletion p.Gly29Alafs*4 [23] c.88C > T Missense p.Pro30Ser [24] c.95T > G Missense p.Val32Gly [25] c.100dupT Duplication p.Cys34Leufs*4 [19] c.100_115del16 Deletion p.Cys34Hisfs*15 [26] c.101G > A Missense p.Cys34Tyr [24] c.102C > A Missense p.Cys34* [25] c.106T > C Missense p.Cys36Arg [14] c.107G > A Missense p.Cys36Tyr [27] c.115_118dupCCAC Duplication p.His40Profs*130 [28] c.121T > C Missense p.Cys41Arg [28] c.128_132delGGCCT Deletion p.Gly43Aspfs*124 [29] c.129delG Deletion p.Pro44Leufs*10 [14] c.136_137delTGinsCT Delins p.Cys46Leu [29] c.138C > A Missense p.Cys46* [19] c.139_140insCG Insertion p.Arg47Profs*8 [30] c.139dupC Duplication p.Arg47Profs*122 [24] Continued c.140G > C Missense p.Arg47Pro [27] c.142G > A Missense p.Gly48Arg [31] c.143G > A Missense p.Gly48Glu [32] c.143_147delGGGCCinsAGCCT Delins p.Gly48_Ala49delinsGluPro [33] c.145dupG Duplication p.Ala49Glyfs*120 [34] c.145delG Deletion p.Ala49Profs*5 [35] c.147delC Deletion p.Trp50Glyfs*4 [36] c.148T > G Missense p.Trp50Gly [37] c.149G > A Missense p.Trp50* [29] c.150G > T Missense p.Trp50Cys [38] c.150G > A Missense p.Trp50* [39] c.152G > A Missense p.Cys51Tyr [34] c.154A > G Missense p.Thr52Ala [24] c.155delC Deletion p.Thr52Lysfs*2 [30] c.164_169delTGGTGC Del...…”

Μεταλλάξεις Του Γονιδίου Της Ενδογλίνης Στην Κληρονομική Αιμορραγική Τηλαγγειεκτασία

“…Αν και πρόκειται για ιδιαίτερα διεισδυτική νόσο (η διεισδυτικότητα υπολογίζεται περίπου σε 97%), μπορεί να μην εμφανιστούν συμπτώματα μέχρι την ηλικία των 30 ετών (7). Η διεισδυτικότητα του φαινοτύπου εξαρτάται από την ηλικία και η εκδήλωση των συμπτωμάτων ολοκληρώνεται περίπου μέχρι την ηλικία των 40 ετών (8,11).…”

“…Η εμφάνισή είναι υψηλότερη σε κάποιες γεωγραφικά απομονωμένες περιοχές φτάνοντας το μέγεθος του 12,5/100.000 στο γαλλικό διαμέρισμα της Ain και στο Haut de Jura1 (1), 5,6/100.000 στην νήσο Funen στη Δανία (9,10,11), και 2,5:100.000 στην περιοχή του Newcastle της Αγγλίας (8). H συχνότερη εμφάνιση της νόσου, μέχρι τώρα, παρουσιάζεται στον αφρο-καραϊβικό πληθυσμό των Ολλανδικών Αντιλλών και φτάνει το 19,4/100.000 (13,14).…”