Molecular screening of<i>ALK1/ACVRL1</i>and<i>ENG</i>genes in hereditary hemorrhagic telangiectasia in France

Lesca, Gaëtan; Plauchu, Henri; Coulet, Florence; Lefèbvre, Sylvain; Plessis, Ghislaine; Odent, S.; Rivière, Sophie; Leheup, Bruno; Goizet, Cyril; Carette, Marie-France; Cordier, Jean-François; Pinson, Stéphane; Soubrier, Florent; Calender, Alain; Giraud, Sophie

doi:10.1002/humu.20017

Cited by 117 publications

(142 citation statements)

References 49 publications

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Section: Resultssupporting

confidence: 86%

“…This latter missense mutation occurred in patient P3 who additionally carried mutation p.Glu379Lys in the ALK1 gene. The other three ENG mutations detected in our patients had been reported by other workers (Gallione et al, 1998;Pece-Barbara et al, 1999;Lesca et al, 2004).According to our literature and database survey, up to the present time ( Chaouat et al, 2004). Together with the one novel ENG mutation detected in this study, the total number of ENG mutations is now 117.…”

supporting

confidence: 76%

“…The latter mutation decreases the Shapiro-Senepathy consensus value (CV) (Shapiro and Senapathy, 1987) from 0.84 (G-allele) to 0.66 (A-allele). Six of the ALK1 mutations detected in this study had been previously described (Berg et al, 1997;Abdalla et al 2000;Trembath et al, 2001;Olivieri et al, 2002;Lesca et al, 2004).In the extracellular domain of the ENG gene, one novel ENG mutation occurred at nucleotide 1844 (C>T) changing codon 615 in the transmembrane domain from serine to leucine. This latter missense mutation occurred in patient P3 who additionally carried mutation p.Glu379Lys in the ALK1 gene.…”

mentioning

confidence: 77%

“…To the best of our knowledge, this is the first case of a HHT patient with mutations in both the ALK1 and the ENG genes. It is likely that the ALK1 mutation p.Glu379Lys (which has recently been identified independently by Lesca et al, 2004) is the predominant disease causing mutation. This substitution of an acidic amino acid by a basic amino acid in the functional important kinase domain of the ALK1 protein is more likely to lead to important functional consequences than the ENG mutation p.Ser615Leu, a substitution of a neutral polar by a neutral nonpolar amino acid in the transmembrane domain.…”

Section: Discussionmentioning

confidence: 99%

“…However, one has to take into account that the overall mutation detection rate in our study was 78%. In a recently published extensive study a detection rate of 68% has been reported in patients with a confirmed diagnosis of Morbus-Osler according to the Curaçao criteria (Lesca et al, 2004). Although we have been sequencing the whole coding sequences of both genes, we can not rule out that we missed mutations like large deletions or insertions, or mutations involving non-coding regions of these genes.…”

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confidence: 99%

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

et al. 2005

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Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involvement is unknown. We screened the two known HHT disease loci, the ALK1 (ACVRL1) and ENG genes, for mutations in a clinically well-characterized group of HHT patients with or without liver involvement. Mutations in the ALK1 gene were detected in eight out of 10 HHT patients with hepatic manifestation. Among nine HHT patients without liver involvement, four had mutations in the ALK1, and three in the ENG genes, respectively. In one patient with hepatic manifestation a mutation was detected in both the ALK1 and ENG genes. No mutation could be detected in two patients with liver involvement and, likewise, in two patients without hepatic manifestation. In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations. © 2005 Wiley-Liss, Inc.KEY WORDS: HHT; Osler-Rendu-Weber syndrome; ALK1; ACVRL1; ENG INTRODUCTIONOsler-Rendu-Weber syndrome or hereditary hemorrhagic telangiectasia (HHT, MIM# 187300 and 600376) is an autosomal dominat disease with age-dependent penetrance and variable expression of the clinical manifestation. The estimated prevalence is in the order of 1 out of 10,000 (Guttmacher et al., 1995). According to the Curaçao DOI: 10.1002/humu.9311 2 Kuehl et al.criteria , the clinical diagnosis of HHT requires that at least three out of four conditions, i.e. epistaxis, telangiectasia, visceral lesions, and a family history with HHT, should be present in order to ensure the diagnosis. While the cutaneous and mucocutaneous manifestations have mostly a relative good prognosis, the involvement of the visceral organs, if untreated, can trigger mortality (Kjeldsen et al., 1999;Shovlin and Letarte, 1999).Hepatic manifestation of HHT is estimated to affect about 8 to 30% of the patients (Reilly and Nostrant, 1984;Bauer et al., 1995;Kjeldsen et al., 1999). The hepatic vascular malformation can be diagnosed by ultrasound (Caselitz et al., 2003) and is mostly associated with fibrosis and/or atypical cirrhosis (Reilly and Nostrant, 1984). In severe cases, the reduced liver function associated with HHT may lead to progressive hepatic failure (Weik and Greiner 1999).Little is known about the genetic basis of the observed clinical heterogeneity of HHT. Even within the same family there could be great variations with respect to manifestation and severity of the disease. (Shovlin, 1997). Disease-causing mutations had been identified in both the endoglin (ENG, MIM# 131195) gene (McAllister et al., 1994) on chromosome 9 (HHT type 1) and in the activin receptor-like kinase (ALK1, also designated ACVRL1, MIM# 601284) gene (Johnson et al., 1996) on chromosome 12 (HHT ...

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Section: Resultssupporting

confidence: 86%

supporting

confidence: 76%

mentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2005

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Vascular abnormalities in the fingers of patients affected with hereditary hemorrhagic telangiectasia (HHT) as assessed by color doppler sonography

Draghi

Precerutti

et al. 2005

American J of Med Genetics Pt A

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Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations*

Bayrak-Toydemir

McDonald

Markewitz

et al. 2006

American J of Med Genetics Pt A

207

227

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Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II-like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed-54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.

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Molecular screening ofALK1/ACVRL1andENGgenes in hereditary hemorrhagic telangiectasia in France

Cited by 117 publications

References 49 publications

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

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

Vascular abnormalities in the fingers of patients affected with hereditary hemorrhagic telangiectasia (HHT) as assessed by color doppler sonography

Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations*

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