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

DBG-Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, The Netherlands.
Human Genetics (Impact Factor: 4.52). 02/2005; 116(1-2):8-16. DOI: 10.1007/s00439-004-1196-5
Source: PubMed

ABSTRACT Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant disorder characterized by an aberrant vascular development. The resulting vascular lesions range from smaller mucocutaneous telangiectases to large visceral arteriovenous malformations, especially in the skin, lung, gastrointestinal tract and the brain. Mutations in the genes encoding endoglin (ENG, chromosome 9q34) and activin A receptor type-like kinase 1 (ALK-1, also named ACVRL1, chromosome 12q13) are associated with HHT1 and HHT2, respectively. We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene. In most of the probands, we found a mutation in one of the two genes: 53% in the ENG gene and 40% in the ALK-1 gene. In 7% of the families no ENG or ALK1 mutation was found. The mutations detected were deletions, insertions, nonsense, missense and splice site mutations. The majority were novel mutations.

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    • "Thus, in Spain, HHT due to the fact that mutation in ALK1 is higher than in ENG, following a similar trend (6 vs 11) as in our previous studies [22]. This is in agreement with the data from other mediterranean populations like France [30] and Italy [31] but different from Canada, USA [18,24] and Northern Europe populations [32] where pathogenetic mutations in ENG are more frequent than in ALK1. "
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    ABSTRACT: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder characterised mainly by mutations in the Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. Here, we have identified 22 ALK1 mutations and 15 ENG mutations, many of which had not previously been reported, in independent Spanish families afflicted with HHT. We identified mutations in thirty-seven unrelated families. A detailed analysis of clinical symptoms was recorded for each patient analyzed, with a higher significant presence of pulmonary arteriovenous malformations (PAVM) in HHT1 patients over HHT2. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG. Missense mutations in ENG and ALK1 were localized in a tridimensional protein structure model. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1) in our Spanish population, in agreement with previous data from our country and other Mediterranean countries (France, Italy), but different to Northern Europe or North America. There was a significant increase of PAVM associated with HHT1 over HHT2 in these families.
    BMC Medical Genetics 02/2008; 9(1):75. DOI:10.1186/1471-2350-9-75 · 2.45 Impact Factor
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    • "The healthy mother of the index case, as expected, does not carry the mutation; the father died because of a pancreatic cancer at age 56, and no biological samples were available for analysis. We then compared our results to the screenings recently published by other groups on different European populations [Germany (Kuehl et al. 2005; Schulte et al. 2005; Wehner et al. 2006), Spain (Fernandez-L et al. 2006), Denmark (Brusgaard et al. 2004), France (Lesca et al. 2004, 2006), Netherlands (Letteboer et al. 2005)] and to the work of Lenato et al. 2006 on a smaller group of Italian patients (see Figs. 1,2). The distribution of the mutations in the two genes [number of ENG mutations/total number of mutations] varied from 37% in Spain to 54% in the Netherlands. "
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    ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder causing vascular dysplasias. About 70-80% of HHT patients carries mutations in ENG or ACVRL1 genes, which code for a TGFbeta receptor type III and I respectively. Molecular data on a large cohort of Italian HHT patients are presented, discussing the significance of missense and splice site mutations. Mutation analysis in ENG and ACVRL1 genes was performed using single strand conformation polymorphisms (SSCP), denaturing high performance liquid chromatography (DHPLC) and subsequent direct sequencing. Overall, 101 mutations were found, with ACVRL1 involved in 71% of cases. The highest number of mutations (28/101 subjects, 14/76 different mutations referring to both genes) was in ACVRL1, exon 3. Mutation analysis was then extended to a total of 356 family members, and 162 proven to carry the mutation. New polymorphisms were identified in both genes, and evidence that ENG P131L change is not a disease-causing mutation was also provided. An in silico analysis was performed in order to characterize splice-site mutations. These results were compared to other European national studies and data from Italy, France and Spain were consistent for an higher incidence of ACVRL1 mutations.
    Journal of Human Genetics 02/2007; 52(10):820-9. DOI:10.1007/s10038-007-0187-5 · 2.53 Impact Factor
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    • "Letteboer et al., 2005) where pathogenetic mutations in ENG are more frequent than in ALK1. We did not find a clear evidence for a more acute symptomatology in HHT1 than HHT2, and the number of pulmonary arteriovenous malformations (PAVMs) and gastrointestinal (GI) bleedings were equally shared by both types. "
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    ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder originated by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. The first large series HHT analysis in Spanish population has identified mutations in 17 unrelated families. Ten different mutations in ALK1 and six in ENG genes were found. Six unrelated families had a mutation in ENG gene, four representing new mutations, p.Y258fs, pV323fs, p.F279fs (c.834_837del CTTC), and p.F279fsdupC. Eleven unrelated families harboured mutations in ALK1; ten were new mutations identified as p.H328P, p.R145fs, p.G68C, p.A377T, p.H297R, p.M376T, p.C36Y, p.H328P, p.T82del and p.R47P. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1), in agreement with data reported for other Mediterranean countries (France, Italy), but at variance with Northern Europe or North America. Endoglin expression in HHT1 or HHT2 activated monocytes and blood outgrowth endothelial cells (BOECs) from older patients was well below the theoretical 50% level expected from the HHT1 haploinsufficiency model, suggesting that the pathogenic endoglin haploinsufficiency leading to the HHT phenotype is age-dependent. Interestingly, ALK1 protein levels of HHT BOECs in some missense ALK1 mutants were similar to controls. In vitro expression of these ALK1 constructs suggests that, in addition to the haploinsufficiency model, certain ALK1 mutants may inhibit the function of the wild type allele.
    Human Mutation 03/2006; 27(3):295. DOI:10.1002/humu.9413 · 5.05 Impact Factor
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