Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred

McDonald, Jamie; Miller, Franklin J.; Hallam, Stephanie; Nelson, Lesa; Marchuk, Douglas A.; Ward, Kenneth

doi:10.1002/1096-8628(20000814)93:4<320::aid-ajmg12>3.0.co;2-r

Cited by 96 publications

(67 citation statements)

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“…A significantly higher liver involvement had also been reported previously for two large HHT2 families (McDonald et al, 2000;Lin et al, 2001). The main objective of the present study is to screen systematically for mutations in the ENG and ALK1 genes of patients with HHT and liver involvement as compared to patients with HHT and no liver disease.…”

Section: Introductionsupporting

confidence: 78%

“…Our results are well in accordance with previous publications on hepatic manifestations in patients with HHT. Although liver involvement was reported for a few patients with ENG mutations, (Berg et al, 2003;Harrison et al, 2003;Cymerman et al, 2003;Shovlin et al, 1997) it was much more often reported for patients carrying mutations in the ALK1 gene (Johnson et al, 1996;Piantanida et al, 1996;Berg et al, 1997;McDonald et al, 2000;Lin et al, 2001;Trembath et al, 2001;Olivieri et al, 2002;Abdalla et al, 2003a & b ;Berg et al, 2003). Liver involvement was not routinely assessed in most of these studies, since the emphasis was mainly on the genotype and not the phenotype, or the reports were on multiple family members and not on unrelated individuals.…”

Section: Resultsmentioning

confidence: 99%

“…It is noteworthy that, even in families with high rates of liver involvement, only a subset of the mutation carriers finally develops hepatic disease (Piantanida et al, 1996;McDonald et al, 2000;Lin et al, 2001; Abdalla et al, 2003b). The phenotypic variability of HHT type 2 is also evident from our study: the same ALK1 mutation (p.Arg67Trp) was present in two unrelated HHT patients, one with (P4), and one without (P13) hepatic manifestation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, pulmonary arteriovenous malformations (PAVM) were only seen in HHT1 (Berg et al, 2003), which confirmed earlier observations . However, PAVMs can also be encountered in some patients with HHT2 (McDonald et al, 2000;Kjeldsen et al, 2001). Furthermore, ALK1 mutations were also identified in families with pulmonary hypertension and HHT (Trembath et al, 2001; Harrison et al, 2002).…”

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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: Introductionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

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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“…17,18 Mutations are distributed throughout the ALK-1 gene. Frameshift and nonsense mutations predict nonsense mediated mRNA decay 27 and failure to produce functional protein.…”

Section: Alk-1 Missense Mutations In Kinase Domainmentioning

confidence: 99%

Disease-associated mutations in conserved residues of ALK-1 kinase domain

et al. 2003

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Activin receptor-like kinase-1 (ALK-1), the gene mutated in HHT type 2 (HHT2), is a serine/threonine kinase receptor type I of the TGF-b superfamily, specifically expressed on endothelial cells. We established an HHT2 genotype in 16 families and report nine novel mutations. These include insertions and deletions of single base pairs in exons 3, 8 and 9, as well as nonsense mutations in exons 4 and 8 of ALK-1, which would lead to premature truncation and unstable mRNA or protein. Three novel missense mutations were identified in exons 7 and 8 of the kinase domain. Five previously reported substitutions were also observed in the families analyzed. Our results bring to 36, the number of mutations associated with HHT2, and are mostly found in exons 8 and 3 followed by exons 4 and 7. To ascertain the potential functional implications of the missense mutations in the ALK-1 kinase domain, we generated a model based on the threedimensional structure of the homologous ALK-5 kinase domain. Our data reveal that the 11 missense mutations modify residues conserved among type I receptors and alter the polarity, charge, hydrophobicity and/or size of the substituted amino-acid and likely lead to misfolded and nonfunctional proteins.

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