Bossler, A. D., Richards, J., George, C., Godmilow, L. & Ganguly, A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum. Mutat. 27, 667-675

Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.
Human Mutation (Impact Factor: 5.14). 07/2006; 27(7):667-75. DOI: 10.1002/humu.20342
Source: PubMed


Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) is an autosomal dominant disease characterized by arteriovenous malformations ranging from cutaneous and mucous membrane telangiectasias to more severe pulmonary, gastrointestinal, and cerebral arteriovenous malformations (AVMs). Acute complications from bleeding or pulmonary shunting may be catastrophic. However, when diagnosed early, the complications can usually be prevented. Mutations in two genes, Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1 or ALK1) have been associated with HHT. We describe the results of mutation analysis on a consecutive series of 200 individuals undergoing clinical genetic testing for HHT. The observed sensitivity of mutation detection was similar to that in other series with strict ascertainment criteria. A total of 127 probands were found, with sequence changes consisting of 103 unique alterations, 68 of which were novel. In addition, eight intragenic rearrangements in the ENG gene and two in the ACVRL1 gene were identified in a subset of coding sequence mutation-negative individuals. Most individuals tested could be categorized by the number of HHT diagnostic criteria present. Surprisingly, almost 50% of the cases with a single symptom were found to have a significant sequence alteration; three of these reported only nosebleeds. Genetic testing can confirm the clinical diagnosis in individuals and identify presymptomatic mutation carriers. As many of the complications of HHT disease can be prevented, a confirmed molecular diagnosis provides an opportunity for early detection of AVMs and management of the disease.

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    • "Mutations in the 5'-UTR are very rare in HHT patients. Bossler et al. reported the c.1-10 C > T mutation in the ENG 5'-UTR of a patient with HHT [31], which is the only known 5'-UTR mutation among reported ACVRL1 and ENG mutations, except large deletion mutations that include the 5'-UTRs [14]. Although the patient with the ENG c.1-10 C > T mutation had recurrent epistaxis, PAVM, and a suggestive family history, no experimental data testing the functionality of the mutant allele was reported. "
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    ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder, characterized by recurrent epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in various visceral organs. Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1; ALK1), receptors for transforming growth factor-β (TGF-β) superfamily, have been identified as the principal HHT-causing genes. Three unrelated Korean HHT patients and their asymptomatic as well as symptomatic family members were genetically diagnosed by sequencing whole exons and their flanking regions of ENG and ACVRL1. Functionality of an aberrant translation start codon, which is created by a substitution mutation at the 5'-untranslated region (UTR) of ENG found in a HHT family, was tested by transient in vitro transfection assay. Decay of the mutant transcripts was also assessed by allele-specific expression analysis. Two ENG and one ACVRL1 mutations were identified: a known ENG mutation (c.360+1G > A; p.Gly74_Tyr120del); a novel ENG mutation (c.1-127C > T); and a novel ACVRL1 mutation (c.252_253insC; p.Val85fsX168). We further validated that the 5'-UTR ENG mutation prevents translation of ENG from the biological translation initiation site of the mutant allele, and leads to degradation of the mutant transcripts. This is the first experimental demonstration that a 5'-UTR mutation can prevent translation of ENG among HHT patients, and further supports the previous notion that haploinsufficiency is the primary mechanism of HHT1. Our data also underscore the importance of including exons encoding 5' UTR for HHT mutation screening.
    BMC Medical Genetics 10/2011; 12(1):130. DOI:10.1186/1471-2350-12-130 · 2.08 Impact Factor
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    • "The majority of HHT cases are due to mutations in either endoglin or ALK1 [Berg et al., 2003; Kjeldsen et al., 2005; Bossler et al., 2006; Letteboer et al., 2006; Bayrak-Toydemir et al., 2006b] but approximately 1–2% of presumptive HHT patients referred for DNA-based diagnostic testing instead carry a mutation in SMAD4 [Gallione et al., 2006]. These patients, presenting initially with HHT but molecularly diagnosed as having JP–HHT, should be considered clinically as if they were at risk for JP and its associated cancer predisposition. "
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    ABSTRACT: Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.
    American Journal of Medical Genetics Part A 02/2010; 152A(2):333-9. DOI:10.1002/ajmg.a.33206 · 2.16 Impact Factor
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    • "Most of the ENG mutations were widely distributed throughout the gene, not indicating any special hot spot areas within the gene. Out of five detected DNA changes, four mutations had been described previously as mutations in the HHT mutation database or recently been published [2,5,20,27,31-35]. The alterations included mainly nucleotide substitutions such as missense, splice site and frameshift mutations. "
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    ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disorder which is clinically characterised by recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations. Genetic linkage studies identified two genes primarily related to HHT: endoglin (ENG) on chromosome 9q33-34 and activin receptor-like kinase1 (ACVRL1) on chromosome 12q13. We have screened a total of 41 unselected German patients with the suspected diagnosis of HHT. Mutation analysis for the ENG and ACVRL1 genes in all patients was performed by PCR amplification. Sequences were then compared to the HHT database sequences of the ENG mRNA (accession no. BC014271.2) and the ACVRL1 mRNA (accession no. NM000020.1). We identified 15 different mutations in 18 cases by direct sequencing. Among these mutations, one novel ENG mutation could be detected which has not yet been described in the literature before. The genotype-phenotype correlation was consistent with a higher frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in patients with ACVRL1 mutations in our collective. For rapid genotyping of mutations and SNPs (single nucleotide polymorphisms) in ENG and ACVRL1, allele-specific PCR methods with sequence-specific primers (PCR-SSP) were established and their value analysed.
    BMC Medical Genetics 02/2009; 10(1):53. DOI:10.1186/1471-2350-10-53 · 2.08 Impact Factor
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