Endoglin gene mutations and polymorphisms in Italian patients with hereditary haemorrhagic telangiectasia

Abstract

Autosomal-dominant hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disease caused by mutations in at least two different loci. We screened for mutations in four Italian families where segregation studies showed clear evidence of linkage to the endoglin (ENG) locus. In addition, one sporadic case and three patients with pulmonary arteriovenous malformations, belonging to small nuclear families unsuitable for linkage analysis, were included in the screening. The proband from each family was investigated using single-strand conformation polymorphism and heteroduplex analysis; potential variants were sequenced. Four novel and one previously reported mutation were detected, as well as three new polymorphisms. The novel mutations included deletions in exon 1 (patient 581/02), exon 5 (patient 780/01) and exon 7 (patient 700/01), and a C-->T229 substitution in exon 3 (patient 462/02). When analysing patient 700/01 and his affected daughter, we encountered a mutant ENG allele with two mutations--a deletion in exon 7 and a substitution in exon 12--which converts isoleucine 575 into threonine, in a non-conserved region. Both mutations were absent in the two healthy sons of the patient, while the polymorphic variant in exon 12 was present in his healthy father. These results and haplotype-segregation studies suggest that a de novo deletion had occurred in the gamete of paternal origin. For the first time the parental germline in which a de novo HHT mutation occurred has been identified.

Hepatic manifestation is associated withALK1 in hereditary hemorrhagic telangiectasia: Identification of five novelALK1 and one novelENG mutations

“…Fifty seven mutations were listed in the recent review by van den Driesche and colleagues (van der Driesche et al, 2003) while 59 further novel mutations have been published subsequently as follows: 31 mutations (Lesca et al, 2004), 17 (Cymerman et al, 2003), 4 (Lastella et al, 2003), 4 (Berg et al, 2003), 2 (Harrison et al, 2003), and 1 (Chaouat et al, 2004). Together with the one novel ENG mutation detected in this study, the total number of ENG mutations is now 117.…”

Pulmonary Arteriovenous Malformations, Hereditary Hemorrhagic Telangiectasia, and Brain Abscess

“…The mutation in case 1 is a nucleotide substitution in the endoglin gene (C → T511), leading to a nonsense mutation (R171X), and has already been described by our group in the same patient [13] and by Shovlin et al [14]. The mutation in case 3 is also a nonsense mutation in the endoglin gene (C → T229; Q77X); this mutation has already been described by our group in the same patient [13]. The mutation in case 5 has never been described previously; it is an insertion in the exon 9A of the endoglin gene (1191–1192insAG), with a frame shift leading to a premature stop codon (Glu397fsX421).…”

Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients

“…To date, more than 111 different mutations have been identified in the ENG gene Lastella et al 2003;Lesca et al 2004), whereas the number of different mutations reported in the ALK-1 gene is 77 (Van den Driesche et al 2003;Lesca et al 2004). Almost all the mutations reported are unique for a particular family.…”