SMAD4 mutations found in unselected HHT patients

Duke University Medical Center, Durham, NC 27710, USA.
Journal of Medical Genetics (Impact Factor: 5.64). 11/2006; 43(10):793-7. DOI: 10.1136/jmg.2006.041517
Source: PubMed

ABSTRACT Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease exhibiting multifocal vascular telangiectases and arteriovenous malformations. The majority of cases are caused by mutations in either the endoglin (ENG) or activin receptor-like kinase 1 (ALK1, ACVRL1) genes; both members of the transforming growth factor (TGF)-beta pathway. Mutations in SMAD4, another TGF-beta pathway member, are seen in patients with the combined syndrome of juvenile polyposis (JP) and HHT (JP-HHT).
We sought to determine if HHT patients without any apparent history of JP, who were undergoing routine diagnostic testing, would have mutations in SMAD4. We tested 30 unrelated HHT patients, all of whom had been referred for DNA based testing for HHT and were found to be negative for mutations in ENG and ALK1.
Three of these people harboured mutations in SMAD4, a rate of 10% (3/30). The SMAD4 mutations were similar to those found in other patients with the JP-HHT syndrome.
The identification of SMAD4 mutations in HHT patients without prior diagnosis of JP has significant and immediate clinical implications, as these people are likely to be at risk of having JP-HHT with the associated increased risk of gastrointestinal cancer. We propose that routine DNA based testing for HHT should include SMAD4 for samples in which mutations in neither ENG nor ALK1 are identified. HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps associated with JP.

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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 · 2.05 Impact Factor
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    • "Intuitively, this makes sense due to the role of Smad4 downstream of BMPR1A/ALK3, ALK1, and Endoglin (see below). A study recently investigated HHT patients that do not carry mutations in Endoglin or ALK1 and have not been diagnosed with combined JP and found that 10% of these cases have mutations in Smad4 (Gallione et al., 2006). Because JP is associated with a high risk of developing gastrointestinal cancers, HHT patients who have not been diagnosed with JP may indeed be afflicted by the combined syndrome and harbor this risk. "
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    ABSTRACT: TGF-beta superfamily signaling pathways emerged with the evolution of multicellular animals, suggesting that these pathways contribute to the increased diversity and complexity required for the development and homeostasis of these organisms. In this review we begin by exploring some key developmental and disease processes requiring TGF-beta ligands to underscore the fundamental importance of these pathways before delving into the molecular mechanism of signal transduction, focusing on recent findings. Finally, we discuss how these ligands act as morphogens, how their activity and signaling range is regulated, and how they interact with other signaling pathways to achieve their specific and varied functional roles.
    Developmental Cell 04/2009; 16(3):329-43. DOI:10.1016/j.devcel.2009.02.012 · 10.37 Impact Factor
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    • "doi:10.1016/j.jhep.2007.12.022 genes, known to modulate the endothelial response to the TGF-b superfamily of ligands, are involved in the process of angiogenesis [4] [5]. Mutations in a third gene, MADH4, have been reported in a subgroup of HHT individuals with or without signs of juvenile polyposis [6]. Additional HHT-causing genes have also recently been mapped to chromosomes 5 [7] and 7 [8]. "
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    ABSTRACT: Hepatic arterio-venous malformations (HAVMs) have been found in 74% of hereditary hemorrhagic telangiectasia (HHT) patients with multislice CT (MSCT). This single-blind study aimed to compare the diagnostic accuracy of echo-color-Doppler with MSCT and identify the most sensitive ultrasound criteria indicating hepatic shunts. One hundred and fifty-three HHT patients were systematically screened for HAVMs by biological tests, abdominal MSCT and echo-color-Doppler. Twenty-five normal subjects and 15 cirrhotic patients were also included as control groups. Both intrahepatic ("color spots" and hypervascularization) and extrahepatic parameters (diameter, flow velocity and tortuosity of hepatic artery and diameter and flow velocity of portal/hepatic vein) were utilized. "Color-spots" are defined as subcapsular vascular spots with a high-velocity arterial blood flow and low resistivity index and can identify extremely small HAVMs. CT was positive in 128/153 (84%) patients and Doppler color spots were found in 131/153 (86%) patients. The sensitivity, specificity and diagnostic accuracy of "color spots" compared to MSCT were 95.3%, 68.0% and 91.8%, respectively. The "color-spot" showed a greater correlation to CT (V(index)=0.655; p<0.0001) than extrahepatic criteria (V=0.317). In 20/29 (69%) subjects, echo-color-Doppler, confirmed by CT, identified the third criterion for definite HHT diagnosis. Intrahepatic criteria was superior to extrahepatic criteria for identification of HAVMs. A new Doppler parameter ("color-spots") with an optimal accuracy for detecting HAVMs is proposed for easy periodic screening of HHT patients.
    Journal of Hepatology 06/2008; 48(5):811-20. DOI:10.1016/j.jhep.2007.12.022 · 10.40 Impact Factor
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