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

Abstract

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 ...

DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population

“…Among the Italian patients, we found a high prevalence of ALK1-mutation-carrier probands (41) compared to that for the ENG-mutation-carrier probands (20). Such results, in agreement with the French (Lesca et al, 2004) and Spanish data (Fernandez-Lopez et al, unpublished data reported in the 6 th HHT Scientific Conference, Lyon, 21-23 April 2005), are in contrast with studies on other populations (Letteboer et al, 2005;Abdalla et al, 2005;Kuehl et al, 2005;Schulte et al, 2005). In the French population described by Lesca et al (2004), the higher prevalence of ALK1 mutations was due to both the founder effect and presence of mutational hot-spots which occurred in ALK1 but not in ENG since the authors observed 36 and 34 different mutations in ALK1 and ENG, respectively.…”

Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences

“…The link between ACVRL1 mutations and a higher prevalence of liver arteriovenous shunts has been suggested from previous, although not all, studies. [21][22][23] We confirm here a close link between ACVRL1 mutations and hepatic involvement but also demonstrate for the first time that the proportion of patients with ACVRL1 mutations increases as the severity of the liver disease increases. Moreover, in our experience, almost all patients investigated for severe liver involvement or referred for liver transplantation carry ACVRL1 mutations (not shown).…”

Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies

“…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, 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).…”