Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2

Johnson, D. W.; Berg, Jonathan; Baldwin, Melanie A.; Gallione, Carol J.; Marondel, Ivonne; Yoon, Sung Joo Kim; Stenzel, Timothy T.; Speer, Marcy C.; Pericak‐Vance, M. A.; Diamond, Austin G.; Guttmacher, Alan E.; Jackson, Charles E.; Attisano, Liliana; Kucherlapati, Raju; Porteous, Mary; Marchuk, Douglas A.

doi:10.1038/ng0696-189

Cited by 1,014 publications

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“…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%

“…(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 type 2). The presence of two disease loci provided the rationale for genotype/phenotype studies of the disease.…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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 endothelial and smooth muscle cells express all the examined type I and II receptors of TGF-b superfamily, indicating that multiple members of TGF-b superfamily may contribute to the maintenance or remodeling of vessel structure (Yang et al 1990;McAllister et al 1994;Dickson et al 1995;Johnson et al 1996). At present, ALK-1 is an orphan receptor.…”

Section: Discussionmentioning

confidence: 99%

“…However, the structure of ALK-1 is very similar to those of the other type I receptors, which suggests that it is a functioning receptor for certain TGF-b superfamily member(s). The mutation of ALK-1 causes hereditary haemorrhagic telangiectasia (type 2), and the mutation of endoglin (TGF-b receptor that modulates TGF-b signaling) causes a similar disease [hereditary haemorrhagic telangiectasia (type 1)] (McAllister et al 1994;Johnson et al 1996). This evidence suggests that ALK-1 acts to preserve the integrity of the vascular structure.…”

Section: Discussionmentioning

confidence: 99%

Expression of transforming growth factor‐β superfamily receptors in rat eyes

Obata¹,

Kaji²,

Yamada³

et al. 1999

Acta Ophthalmologica Scandinavica

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“…A total of 11 µl of RNA from each sample (4 µg) were retro-transcribed using 200 U of MMLV-RT (Promega, Madison WI, USA), 1 µl of Random primers (Promega, Madison WI, USA) and 20 U of RNAsin RNAse Inhibitors (Promega, Madison WI, USA). The cDNA was amplified using 3.5 U of Taq Expand Long Template PCR System (Roche Diagnostic, Germany), Taq Expand Long Template Buffer 2 (Roche Diagnostic GmbH, Mannheim, Germany), and exonic primers ALK1cDNA4F and ALK1cDNA8R (Johnson et al, 1996). Bands were visualized on both polyacrylamide and agarose gel, eluted using QIAquick Gel extraction kit (QIAGEN) and cloned in a TOPOPCR2.1 TA-cloning system (Invitrogen Inc, USA).…”

Section: Mutation Analysismentioning

confidence: 99%