Original Article
Clinical and Molecular Genetic Features of Pulmonary Hypertension in Patients with Hereditary Hemorrhagic Telangiectasia
N Engl J Med 2001; 345:325-334August 2, 2001
- Abstract
Background
Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor β (TGF-β) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients.
Methods
We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-β–receptor proteins, including endoglin and activin-receptor–like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations.
Results
We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor–like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor–like kinase 1 in normal and diseased pulmonary arteries.
Conclusions
Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.
Media in This Article
Figure 3
Pedigrees of Families 2, 3, 4, 5, and 6 with Coexisting Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia.Figure 1
Signaling Pathway of the Transforming Growth Factor β (TGF-β) Superfamily.Article Activity
- Article
Pulmonary hypertension, defined as the sustained elevation of mean pulmonary arterial pressure above 25 mm Hg at rest and 30 mm Hg during exercise, is a major cause of progressive right-sided heart failure leading to premature death.1 Pulmonary hypertension often results from chronic lung disease leading to hypoxemia, recurrent thromboembolism, or left-sided heart disease, but the pathogenesis is poorly understood. Less commonly, a primary defect of the pulmonary arterial vasculature — characterized by increased medial thickness, intimal fibrosis, and plexiform lesions of capillary-like channels — causes occlusion of small pulmonary arteries, a condition known as primary pulmonary hypertension.2,3
Primary pulmonary hypertension has an incidence of 1 to 2 cases per million people per year.4 The disease may occur at any age but has a peak onset in the third decade of life. Untreated patients with this progressive condition have a median survival of less than three years after diagnosis.5 At least 6 percent of patients with primary pulmonary hypertension have a family history of the condition.4 Kindreds demonstrate autosomal dominant inheritance with markedly reduced penetrance of the gene associated with primary pulmonary hypertension; a proportion of those who inherit the gene have no symptoms.6 The gene for primary pulmonary hypertension, which encodes bone morphogenetic protein receptor II (BMPR2) and is located on human chromosome 2,7-9 is a member of the transforming growth factor β (TGF-β) superfamily of receptors (Figure 1Figure 1
Signaling Pathway of the Transforming Growth Factor β (TGF-β) Superfamily.).10-12 Pulmonary hypertension that is clinically and histologically indistinguishable from primary pulmonary hypertension may occur in persons with hereditary hemorrhagic telangiectasia, an autosomal dominant vascular dysplasia.13,14 Abnormalities in endothelial cells in patients with hereditary hemorrhagic telangiectasia are associated with mucocutaneous telangiectases. These lead to recurrent epistaxis and gastrointestinal blood loss as well as arteriovenous malformations, particularly in the pulmonary, hepatic, and cerebral circulations.15 Pulmonary arteriovenous malformations create clinically significant right-to-left shunts, causing hypoxemia, paradoxical embolism, stroke, and cerebral abscesses.16 Mutations in two genes encoding additional TGF-β receptors — namely, endoglin and activin-receptor–like kinase 1 (ALK1) — which are located on chromosomes 9 and 12, respectively, underlie hereditary hemorrhagic telangiectasia (Figure 1).12,17,18
We investigated the genetic basis of pulmonary hypertension in subjects with hereditary hemorrhagic telangiectasia. We identified kindreds affected by hereditary hemorrhagic telangiectasia and pulmonary hypertension, determined the clinical and pathological features of the cohort, and then searched for molecular genetic defects within the TGF-β–receptor pathway. The analysis was undertaken by the University of Leicester, Leicester, United Kingdom, which holds the data.
Methods
Clinical Evaluation
Written informed consent was obtained from all participants in accordance with the requirements of the ethics committees of the Leicestershire Health Authority, United Kingdom, and the Ministry of Health, Auckland, New Zealand, and the institutional review board of the Vanderbilt University Medical Center. Between April and September 2000, all family members underwent pedigree analysis and clinical assessment. Hereditary hemorrhagic telangiectasia was diagnosed with the use of current international consensus criteria. These require the presence of any three of the following: an affected first-degree relative, recurrent spontaneous epistaxis, mucocutaneous telangiectasia, and documented visceral manifestations.19 The diagnosis of pulmonary hypertension was determined through clinical evaluation, chest radiography, electrocardiography, Doppler echocardiography, right-heart catheterization, and histologic examination of tissue obtained by excision of a lung or at autopsy. Other known causes of elevated pulmonary arterial pressure (for example, chronic lung disease associated with hypoxemia, thromboembolism, intracardiac shunting, and left ventricular failure) were excluded. The diagnosis was established without knowledge of genotypic status. To determine the prevalence of mutations in ALK1 in subjects with primary pulmonary hypertension who had no personal or family history of hereditary hemorrhagic telangiectasia, we also assessed 11 subjects with familial primary pulmonary hypertension and 24 subjects with sporadic primary pulmonary hypertension, in whom the results of analysis for mutations in BMPR2 were negative; the clinical features of these subjects have previously been described.20,21
Genetic Studies
Linkage Analysis
DNA was isolated from peripheral-blood lymphocytes, paraffin-embedded lung tissue, or dried blood spots from family members as indicated in Figure 2Figure 2
Segregation of the Cytosine-to-Thymine Mutation at Position 1450 in ALK1 with Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia in Family 1. and Figure 3Figure 3Pedigrees of Families 2, 3, 4, 5, and 6 with Coexisting Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia..22,23 Genetic-linkage analysis was performed in the largest families, Family 1 and Family 2, with the use of the following polymorphic microsatellite markers: D9S60, D9S315, and D9S61 for endoglin; D12S347, D12S368, and D12S325 for ALK1; and D2S2289, D2S346, and D2S3009 for BMPR2, as previously described.24 Two-point lod scores were calculated with the use of the MLINK program.25 Identification of Mutations in ALK1 and BMPR2
The protein-coding sequence of ALK1 (exons 2 through 10) was amplified from genomic DNA with the use of primers complementary to the intronic sequences near the intron–exon boundaries, as previously described.26
The fragments were amplified by the polymerase chain reaction (PCR) and excess primer was removed from the amplified fragments with the use of a purification kit (QIAquick, Qiagen, Crawley, West Sussex, United Kingdom) and sequenced with a dye-terminator cycle-sequencing system (ABI PRISM 377, Perkin–Elmer Applied Biosystems, Foster City, Calif.). Analysis of BMPR2 sequence (exons 1 through 13) and gene dosage (exons 1 and 12) was performed in each family member with pulmonary hypertension as previously described10,21 (information on primer sequences is available as Supplementary Appendix 1
Supplementary Appendix 1. BMPR2 Genomic Primers. with the full text of this article at http://www.nejm.org).Confirmation of Mutations and Segregation of Genotypes
Identified variants of ALK1 were confirmed by resequencing of independent samples or, for the substitution of thymine for cytosine at position 1450 (Family 1) and the deletion of cytosine at position 37 (Family 5), by restriction-enzyme digestion with Fnu4HI. For the latter, the required exons were amplified, digested with restriction enzyme, and size-fractionated on a 3 percent agarose gel. The presence or absence of sequence variants in DNA samples from family members and from 75 normal controls was also ascertained by sequence analysis or restriction-enzyme digestion.
Histologic and Immunohistochemical Analysis
Normal lung tissue was obtained from unused material excised from donors for heart–lung transplantation and diseased lung from four subjects in Families 1 and 3 (Table 1Table 1
Clinical Features and Mutations in Subjects with Pulmonary Hypertension and a Personal or Family History of Hereditary Hemorrhagic Telangiectasia.). For immunohistochemical analysis, sections were incubated at a dilution of 1:80 with either a polyclonal antibody against activin-receptor–like kinase 1 (provided by Dr. D. Marchuk) or the monoclonal anti–endothelial-cell marker anti-CD31 (JC/70A, from Dako, Ely, Cambridgeshire, United Kingdom) for 60 minutes at room temperature and washed before incubation with biotinylated secondary antibody. Antigen was visualized with the use of the avidin–biotin–peroxidase technique (Vectastain ABC, Vector Laboratories, Peterborough, United Kingdom) with diaminobenzidine substrate. The specificity of immunostaining was demonstrated by the absence of signal in sections incubated with control mouse IgG (Sigma, St. Louis) or in sections processed after omission of the primary antibody.Results
We identified five kindreds (Families 1, 2, 3, 4, and 6) and one individual patient (in Family 5) (Figure 2 and Figure 3) affected by hereditary hemorrhagic telangiectasia, among whom there were 10 cases of pulmonary hypertension (Table 1). Stigmata of hereditary hemorrhagic telangiectasia were not observed in five of these subjects, each of whom was less than 30 years of age (Table 1). Family 1 was noteworthy for the early age of onset of pulmonary hypertension in three members (Table 1 and Figure 2). Pulmonary arteriovenous malformations were detected in Subject II-1 from Family 3 and Subject II-1 from Family 5; in the latter subject, the malformation was embolized after the onset of pulmonary hypertension. In the remaining eight subjects with pulmonary hypertension, pulmonary arteriovenous malformations were ruled out through a combination of chest radiography, high-resolution helical computed tomography of the thorax, studies of arterial oxygen saturation, and pulmonary angiography and hemodynamic studies or were excluded on examination of excised lung tissue or at autopsy.
Analysis of three polymorphic markers on chromosome 12 supported linkage of the disease to the ALK1 locus in two families (likelihood of independent coinheritance, 1 in 100 and 1 in 125 in Families 1 and 2, respectively). Because mutations in ALK1 are known to cause hereditary hemorrhagic telangiectasia, the nine exons encoding the protein product were amplified and sequenced in probands with pulmonary hypertension from five families (Families 1, 2, 3, 4, and 6) and one subject from Family 5. Novel heterozygous sequence variants of ALK1 were identified in the genomes of probands in four of five kindreds (Families 1, 2, 3, and 4) and one subject from Family 5 who had been adopted and had no available family history (Table 1 and Figure 4Figure 4
ALK1 and Identified Mutations.). A deletion of a single nucleotide (cytosine) at position 37 in exon 2 in Subject II-1 from Family 5 and a substitution (thymine for cytosine) at position 1468 in exon 10 in Family 4 are predicted to lead to premature truncation of the mature protein, by changing the reading frame and by introducing a stop codon, respectively.Three sequence variants lead to alterations in 1 of the 503 amino acids of the activin-receptor–like kinase 1: a deletion of an aspartic acid at position 254 encoded by exon 6 (Family 3), a substitution of tryptophan for arginine at position 411 encoded by exon 8 (Family 2), and a substitution of tryptophan for arginine at position 484 encoded by exon 10 (Family 1) (Table 1). No mutations in ALK1 were detected in 11 subjects with familial cases and 24 subjects with sporadic cases of isolated primary pulmonary hypertension, who were known to be negative for mutations in BMPR2.
In Family 6, a previously reported ALK1 sequence variant was detected in Subject III-2, who had hereditary hemorrhagic telangiectasia (Figure 3).26 However, segregation analysis demonstrated that this ALK1 variant was not inherited by Subjects IV-3, V-1, and V-2 (Figure 3). To investigate the genetic basis of the pulmonary hypertension in Subject V-1 further, we performed mutational analysis of BMPR2, A partial deletion in BMPR2 that included exon 12 was identified and shown to be maternally inherited (Table 1). Subject IV-4, who was from an unrelated family, reported no personal or family history of pulmonary hypertension, in keeping with the low penetrance of mutant BMPR2 alleles.10,20,29 Thus, the presence of both ALK1-associated hereditary hemorrhagic telangiectasia and BMPR2-related pulmonary hypertension in Family 6 may be due to chance alone. No mutations in BMPR2 were identified in probands with pulmonary hypertension from Families 1, 2, 3, and 4 or in Subject II-1 from Family 5.
To support the likelihood that these novel variants of ALK1 cause disease, we first confirmed that each variant cosegregated with the disease in available affected family members, as shown for Family 1 (Figure 2). None of the five defects in ALK1 were found in 150 normal chromosomes; therefore, they are unlikely to represent silent polymorphisms. Each of the amino acid alterations has been conserved through evolution and across related type I receptors of the TGF-β superfamily (Figure 4).
Histologic assessment of the pulmonary vasculature was available for four patients from Families 1 and 3. Each had characteristic features of end-stage plexogenic pulmonary hypertension similar to those seen in patients with primary pulmonary hypertension (Figure 5Figure 5
Photomicrographs of Paraffin-Embedded Lung Sections from a Control Subject (Panel A) and Subjects with Plexogenic Pulmonary Hypertension and Mutations in ALK1 (Panels B, C, D, E, and F).).2 Immunohistochemical analysis demonstrated expression of activin-receptor–like kinase 1 to be predominantly in the vascular endothelium of normal and diseased lungs (Figure 5); activin-receptor–like kinase 1 colocalized with the CD31 endothelial-cell marker in serial sections. Expression of activin-receptor–like kinase 1 was also observed in the endothelium of occlusive and plexiform lesions (Figure 5).In our study the clinical, hemodynamic, and histologic features of pulmonary hypertension associated with mutations in ALK1 were indistinguishable from the features of pulmonary hypertension due to occlusive vascular lesions associated with defects in BMPR2 (Figure 5).10,11,20,21
Discussion
The histologic and pathophysiological features of hereditary hemorrhagic telangiectasia and primary pulmonary hypertension might seem to be distinct. Pulmonary arteriovenous dilatation is the hallmark of lung involvement in hereditary hemorrhagic telangiectasia, leading to decreased pulmonary vascular resistance and increased cardiac output, with normal to low pulmonary arterial pressure.14,30 In contrast, primary pulmonary hypertension is characterized by obliteration of small pulmonary arteries, leading to increased pulmonary vascular resistance, marked elevation of pulmonary arterial pressure, and ultimately, a reduction in cardiac output.1
We identified a total of 10 subjects with pulmonary hypertension from 5 families with hereditary hemorrhagic telangiectasia and 1 subject with no available family history. In each of these subjects, we excluded left-ventricular high-output failure secondary to systemic arteriovenous malformations and thromboembolic disease after estrogen therapy for telangiectases12,13 as potential causes of elevated pulmonary arterial pressure. Of the four subjects from whom lung tissue was available (Table 1), pulmonary arterial lesions similar to those reported among subjects harboring mutations in BMPR2 were observed (Figure 5).2 Since the clinical and histologic features of these subjects resembled those of subjects with primary pulmonary hypertension, we considered the possibility that the association with hereditary hemorrhagic telangiectasia reflected basic defects underlying the inherited predisposition to pulmonary hypertension.
Molecular analysis of these kindreds demonstrated that mutations in ALK1 may lead to occlusion of the pulmonary arteries together with vascular dilatation manifested as telangiectasia and arteriovenous malformations. This apparent dichotomy may be explained in part by current knowledge of the TGF-β signaling pathway (Figure 1). After ligand binding, a type II receptor (for example, bone morphogenetic protein receptor II) forms a heteromeric complex with a type I receptor (for example, activin-receptor–like kinase 1) and may associate with an accessory receptor such as endoglin. This results in activation of the kinase domain of the type I receptor, initiating phosphorylation of cytoplasmic proteins and subsequent gene transcription.31
Immunohistochemical analysis demonstrated the presence of activin-receptor–like kinase 1 in diseased pulmonary vascular endothelium, suggesting that this cell type is critical to the pathogenesis of both hereditary hemorrhagic telangiectasia and pulmonary hypertension. TGF-β signaling affects both vascular differentiation and proliferation, and overexpression of the TGF-β1 ligand promotes intimal growth and apoptosis simultaneously in vascular endothelium.32 The pleiotropic nature of TGF-β as a growth factor offers a potential explanation for the variable complications of hereditary hemorrhagic telangiectasia. The net effect of dysfunction of activin-receptor–like kinase 1 may depend on local vascular interactions and other environmental or genetic factors.
The majority of defects in BMPR2 in patients with primary pulmonary hypertension are predicted to generate either a substantially truncated protein or a reduction in the functional activity of the mature protein, a mechanism known as haploinsufficiency.21 The deletion of the cytosine residue at position 37 in ALK1 is predicted to result in a markedly abbreviated transcript, suggesting that a similar mechanism perturbs the function of activin-receptor–like kinase 1 in inherited pulmonary hypertension associated with hereditary hemorrhagic telangiectasia. No mutations in ALK1 were identified in 35 subjects with isolated primary pulmonary hypertension.
The management of pulmonary hypertension in patients with mutations in ALK1 should include a careful assessment for recognized complications of hereditary hemorrhagic telangiectasia. Pulmonary arteriovenous malformations are considered to be more common among patients with defects in endoglin, 33 yet we identified such lesions in two subjects with mutations in ALK1. The possibility of pulmonary as well as systemic vascular malformations should be considered in all patients with hereditary hemorrhagic telangiectasia, irrespective of genotype. Similarly, the possibility of hereditary hemorrhagic telangiectasia should be considered in any patient who presents with unexplained pulmonary hypertension.
Our findings suggest that the TGF-β signaling pathway is an important mechanism for the pathogenesis of pulmonary hypertension. Defects in activin-receptor–like kinase 1 may trigger divergent signaling pathways that remodel the pulmonary artery, resulting in dilated and occlusive vascular phenotypes. Genes that encode other components of the TGF-β pathway, or those that are transcriptionally regulated by the pathway, might also be associated with pulmonary hypertension.
Supported by grants from the British Heart Foundation (RG/2000012, to Drs. Trembath and Morrell) and the National Institutes of Health (HL61997, to Drs. Nichols and Loyd, and HL48164, to Dr. Loyd). Dr. Thomson is the recipient of a Clinical Training Fellowship from the Medical Research Council of the United Kingdom.
We are indebted to the patients and their families for their participation; to Drs. R. Radley-Smith and J. Neutze for their assistance in identifying families; to Drs. B. Merrick, S. Stewart, and M. Burke for histologic analysis; and to Professor I. Young for critical reading of the manuscript.
Source Information
From the Division of Medical Genetics, Departments of Medicine and Genetics, University of Leicester, Leicester, United Kingdom (R.C.T., J.R.T., R.D.M., N.V.M.); the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom (C.A., N.W.M.); the Department of Molecular Medicine, School of Medicine, University of Auckland, Auckland, New Zealand (I.W.); the Service de Pneumologie, Hôpital Antoine Béclère, Assistance Publique–Hôpitaux de Paris, Université Paris-Sud, Clamart, France (G.S., M.H.); the Institute of Cardiology, University of Bologna, Bologna, Italy (N.G.); Vanderbilt University Medical Center, Nashville (J.E.L.); and the Division of Human Genetics, Children's Hospital Medical Center, Cincinnati (W.C.N.).
Address reprint requests to Dr. Trembath at the Division of Medical Genetics, Departments of Medicine and Genetics, Adrian Bldg., University of Leicester, Leicester LE1 7RH, United Kingdom, or at rtrembat@hgmp.mrc.ac.uk.
Other authors were Jonathan Berg, M.D., Department of Clinical Genetics, Guy's Hospital Campus, King's College, London; Alessandra Manes, M.D., Institute of Cardiology, University of Bologna, Bologna, Italy; Julie McGaughran, M.D., Department of Molecular Medicine, School of Medicine, University of Auckland, Auckland, New Zealand; Michael Pauciulo, B.Sc., Division of Human Genetics, Children's Hospital Medical Center, Cincinnati; and Lisa Wheeler, B.Sc., Vanderbilt University Medical Center, Nashville.
- References
References
1
Rubin LJ . Primary pulmonary hypertension. N Engl J Med 1997;336:111-117
Full Text | Web of Science | Medline2
Pietra GG ,Edwards WD ,Kay JM , et al. Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989;80:1198-1206
CrossRef | Web of Science | Medline3
Cool CD ,Stewart JS ,Werahera P , et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers: evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 1999;155:411-419
CrossRef | Web of Science | Medline4
Rich S ,Dantzker DR ,Ayres SM , et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-223
Web of Science | Medline5
D'Alonzo GE ,Barst RJ ,Ayres SM , et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343-349
Web of Science | Medline6
Loyd JE ,Primm RK ,Newman JH . Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis 1984;129:194-197
Web of Science | Medline7
Nichols WC ,Koller DL ,Slovis B , et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 1997;15:277-280
CrossRef | Web of Science | Medline8
Morse JH ,Jones AC ,Barst RJ ,Hodge SE ,Wilhelmsen KC ,Nygaard TG . Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 1997;95:2603-2606
Web of Science | Medline9
Machado RD ,Pauciulo MW ,Fretwell N , et al. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. Genomics 2000;68:220-228
CrossRef | Web of Science | Medline10
International PPH Consortium, Lane KB, Machado RD, et al
CrossRef | Web of Science | Medline11
Deng Z ,Morse JH ,Slager SL , et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-744
CrossRef | Web of Science | Medline12
Blobe GC ,Schiemann WP ,Lodish HF . Role of transforming growth factor β in human disease. N Engl J Med 2000;342:1350-1358
Full Text | Web of Science | Medline13
Sapru RP ,Hutchison DC ,Hall JI . Pulmonary hypertension in patients with pulmonary arteriovenous fistulae. Br Heart J 1969;31:559-569
CrossRef | Web of Science | Medline14
Trell E ,Johansson BW ,Linell F ,Ripa J . Familial pulmonary hypertension and multiple abnormalities of large systemic arteries in Osler's disease. Am J Med 1972;53:50-63
CrossRef | Web of Science | Medline15
Guttmacher AE ,Marchuk DA ,White RI Jr . Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333:918-924
Full Text | Web of Science | Medline16
Shovlin CL ,Letarte M . Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999;54:714-729
CrossRef | Web of Science | Medline17
McAllister KA ,Grogg KM ,Johnson DW , et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994;8:345-351
CrossRef | Web of Science | Medline18
Johnson DW ,Berg JN ,Baldwin MA , et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189-195
CrossRef | Web of Science | Medline19
Shovlin CL ,Guttmacher AE ,Buscarini E , et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66-67
CrossRef | Web of Science | Medline20
Thomson JR ,Machado RD ,Pauciulo MW , et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37:741-745
CrossRef | Web of Science | Medline21
Machado RD ,Pauciulo MW ,Thomson JR , et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001;68:92-102
CrossRef | Web of Science | Medline22
Coyle B ,Coffey R ,Armour JA , et al. Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4. Nat Genet 1996;12:421-423
CrossRef | Web of Science | Medline23
Makowski GS ,Davis EL ,Nadeau F ,Hopfer SM . Polymerase chain reaction amplification of Guthrie card deoxyribonucleic acid: extraction of nucleic acid from filter matrices. Ann Clin Lab Sci 1998;28:254-259
Web of Science | Medline24
Gausden E ,Coyle B ,Armour JA , et al. Pendred syndrome: evidence for genetic homogeneity and further refinement of linkage. J Med Genet 1997;34:126-129
CrossRef | Web of Science | Medline25
Cottingham RW Jr ,Idury RM ,Schaffer AA . Faster sequential genetic linkage computations. Am J Hum Genet 1993;53:252-263
Web of Science | Medline26
Berg JN ,Gallione CJ ,Stenzel TT , et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet 1997;61:60-67
CrossRef | Web of Science | Medline27
Klaus DJ ,Gallione CJ ,Anthony K , et al. Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Hum Mutat 1998;12:137-137 abstract.
CrossRef | Medline28
Abdalla SA ,Pece-Barbara N ,Vera S , et al. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet 2000;9:1227-1237
CrossRef | Web of Science | Medline29
Thomson JR ,Trembath RC . Primary pulmonary hypertension: the pressure rises for a gene. J Clin Pathol 2000;53:899-903
CrossRef | Web of Science | Medline30
Whyte MK ,Hughes JM ,Jackson JE , et al. Cardiopulmonary response to exercise in patients with intrapulmonary vascular shunts. J Appl Physiol 1993;75:321-328
Web of Science | Medline31
Massague J . TGF-beta signal transduction. Annu Rev Biochem 1998;67:753-791
CrossRef | Web of Science | Medline32
Schulick AH ,Taylor AJ ,Zuo W , et al. Overexpression of transforming growth factor beta 1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia. Proc Natl Acad Sci U S A 1998;95:6983-6988
CrossRef | Web of Science | Medline33
Berg JN ,Guttmacher AE ,Marchuk DA ,Porteous ME . Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet 1996;33:256-257
CrossRef | Web of Science | Medline
- Citing Articles (157)
Citing Articles
1
Martin Caselitz, Siegfried Wagner, Michael P. Manns. 2012. Liver Involvement in Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia). , 822-833.
CrossRef2
M. Jerkic, M. G. Kabir, A. Davies, L. X. Yu, B. A. S. McIntyre, N. W. Husain, M. Enomoto, V. Sotov, M. Husain, M. Henkelman, J. Belik, M. Letarte. (2011) Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress. Cardiovascular Research 92:3, 375-384
CrossRef3
Laura Brenner, Wendy K. Chung. 2011. Clinical and Molecular Genetic Features of Hereditary Pulmonary Arterial Hypertension. .
CrossRef4
Allan Lawrie, Abdul G. Hameed, Janet Chamberlain, Nadine Arnold, Aneurin Kennerley, Kay Hopkinson, Josephine Pickworth, David G. Kiely, David C. Crossman, Sheila E. Francis. (2011) Paigen Diet–Fed Apolipoprotein E Knockout Mice Develop Severe Pulmonary Hypertension in an Interleukin-1–Dependent Manner. The American Journal of Pathology 179:4, 1693-1705
CrossRef5
Hala El Chami, Paul M. Hassoun. 2011. Inflammatory Mechanisms in the Pathogenesis of Pulmonary Arterial Hypertension. .
CrossRef6
Maria Klara Frey, Irene Lang. (2011) Pulmonale Hypertension. Wiener klinische Wochenschrift Education 6:3, 78-93
CrossRef7
Johann Strumpher, Eric Jacobsohn. (2011) Pulmonary Hypertension and Right Ventricular Dysfunction: Physiology and Perioperative Management. Journal of Cardiothoracic and Vascular Anesthesia 25:4, 687-704
CrossRef8
N. Hatton, T. Frech, B. Smith, A. Sawitzke, M. B. Scholand, B. Markewitz. (2011) Transforming growth factor signalling: a common pathway in pulmonary arterial hypertension and systemic sclerosis. International Journal of Clinical Practice 65, 35-43
CrossRef9
Byung-Gyu Kim, Ji-Hyun Lee, Jiro Yasuda, Hyun-Mo Ryoo, Je-Yoel Cho. (2011) Phospho-Smad1 modulation by nedd4 e3 ligase in BMP/TGF-β signaling. Journal of Bone and Mineral Research 26:7, 1411-1424
CrossRef10
Jamie McDonald, Pinar Bayrak-Toydemir, Reed E. Pyeritz. (2011) Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Genetics in Medicine 13:7, 607-616
CrossRef11
M Eyries, F Coulet, B Girerd, D Montani, M Humbert, P Lacombe, T Chinet, L Gouya, J Roume, MM Axford, CE Pearson, F Soubrier. (2011) ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clinical Geneticsno-no
CrossRef12
Ralph T. Schermuly, Hossein A. Ghofrani, Martin R. Wilkins, Friedrich Grimminger. (2011) Mechanisms of disease: pulmonary arterial hypertension. Nature Reviews Cardiology 8:8, 443-455
CrossRef13
Tamera J. Corte, Theresa A. McDonagh, Stephen J. Wort. (2011) Pulmonary hypertension in left heart disease: A review. International Journal of Cardiology
CrossRef14
Stephen C Mathai, Paul M Hassoun. (2011) Pulmonary arterial hypertension associated with systemic sclerosis. Expert Review of Respiratory Medicine 5:2, 267-279
CrossRef15
Nada Kherbeck, Mathieu C. Tamby, Guillaume Bussone, Hanadi Dib, Frederic Perros, Marc Humbert, Luc Mouthon. (2011) The Role of Inflammation and Autoimmunity in the Pathophysiology of Pulmonary Arterial Hypertension. Clinical Reviews in Allergy & Immunology
CrossRef16
Sung-A Chang, Shin Yi Jang, Chang-Seok Ki, I-Seok Kang, Duk-Kyung Kim. (2011) Successful bosentan therapy for pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia. Heart and Vessels 26:2, 231-234
CrossRef17
Nicole Pfarr, Justyna Szamalek-Hoegel, Christine Fischer, Katrin Hinderhofer, Christian Nagel, Nicola Ehlken, Henning Tiede, Horst Olschewski, Frank Reichenberger, Ardeschir HA Ghofrani, Werner Seeger, Ekkehard Grünig. (2011) Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respiratory Research 12:1, 99
CrossRef18
Rajamma Mathew. (2011) Cell-Specific Dual Role of Caveolin-1 in Pulmonary Hypertension. Pulmonary Medicine 2011, 1-12
CrossRef19
Mark Geraci, Barbara Meyrick. 2011. Genomics and Proteomics of Pulmonary Vascular Disease. .
CrossRef20
Peter Dorfmüller, Marie-Camille Chaumais, Maria Giannakouli, Ingrid Durand-Gasselin, Nicolas Raymond, Elie Fadel, Olaf Mercier, Frédéric Charlotte, David Montani, Gérald Simonneau, Marc Humbert, Frédéric Perros. (2011) Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension. Respiratory Research 12:1, 119
CrossRef21
Norifumi Nakanishi. (2011) 2009 ESC/ERS Pulmonary Hypertension Guidelines and Connective Tissue Disease. Allergology International 60:4, 419-424
CrossRef22
Satyan Lakshminrusimha, Vasanth H. Kumar. 2011. Diseases of Pulmonary Circulation. , 632-656.
CrossRef23
Bryan Corrin, Andrew G. Nicholson. 2011. Vascular disease. , 401-457.
CrossRef24
Bryan Corrin, Andrew G. Nicholson. 2011. Pulmonary manifestations of systemic disease. , 471-507.
CrossRef25
Claire L. Shovlin. (2010) Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment. Blood Reviews 24:6, 203-219
CrossRef26
Stephen Y Chan, Joseph Loscalzo. 2010. Pulmonary Vascular Disease Related to Hemodynamic Stress in the Pulmonary Circulation. .
CrossRef27
Tamara Tajsic, Nicholas W. Morrell. 2010. Smooth Muscle Cell Hypertrophy, Proliferation, Migration and Apoptosis in Pulmonary Hypertension. .
CrossRef28
Michael G Risbano, Christina A. Meadows, Christopher D. Coldren, Tiffany J. Jenkins, Michael G. Edwards, David Collier, Wendy Huber, Douglas G. Mack, Andrew P. Fontenot, Mark W. Geraci, Todd M Bull. (2010) Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma-Associated Pulmonary Hypertension. Clinical and Translational Science 3:5, 210-218
CrossRef29
N. Ricard, M. Bidart, C. Mallet, G. Lesca, S. Giraud, R. Prudent, J.-J. Feige, S. Bailly. (2010) Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood 116:9, 1604-1612
CrossRef30
Toshikazu Araoka, Hideharu Abe, Tatsuya Tominaga, Akira Mima, Takeshi Matsubara, Taichi Murakami, Seiji Kishi, Kojiro Nagai, Toshio Doi. (2010) Transcription factor 7-like 2 (TCF7L2) regulates activin receptor-like kinase 1 (ALK1)/Smad1 pathway for development of diabetic nephropathy. Molecules and Cells 30:3, 209-218
CrossRef31
H. Beppu. (2010) Transgenic and knockout mouse models for pulmonary hypertension: role of BMPR2. Drug Discovery Today: Disease Models 7:3-4, 61-65
CrossRef32
Kleber Yotsumoto Fertrin, Fernando Ferreira Costa. (2010) Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment. Expert Review of Hematology 3:4, 443-458
CrossRef33
Duncan J. Stewart, Dominique Yelle. (2010) New insights into the molecular pathogenesis of pulmonary arterial hypertension: Relevance to novel therapeutic strategies. Canadian Journal of Cardiology 26, 29B-32B
CrossRef34
M. Toshner, T. Tajsic, N. W. Morrell. (2010) Pulmonary hypertension: advances in pathogenesis and treatment. British Medical Bulletin 94:1, 21-32
CrossRef35
J. P. Burke, R. W. G. Watson, J. J. Mulsow, N. G. Docherty, J. C. Coffey, P. R. O'Connell. (2010) Endoglin negatively regulates transforming growth factor β1-induced profibrotic responses in intestinal fibroblasts. British Journal of Surgery 97:6, 892-901
CrossRef36
Y. M. Law, C. L. Mack, R. J. Sokol, M. Rice, L. Parsley, D. Ivy. (2010) Cardiopulmonary manifestations of portovenous shunts from congenital absence of the portal vein: Pulmonary hypertension and pulmonary vascular dilatation. Pediatric Transplantationno-no
CrossRef37
Steven H. Abman. (2010) Pulmonary hypertension in children: A historical overview. Pediatric Critical Care Medicine 11, S4-S9
CrossRef38
H Wang, Q-Q Cui, K Sun, L Song, Y-B Zou, X-J Wang, L Jia, X Liu, S Gao, C-N Zhang, R-T Hui. (2010) Identities and frequencies of BMPR2 mutations in Chinese patients with idiopathic pulmonary arterial hypertension. Clinical Genetics 77:2, 189-192
CrossRef39
Tina T. Ng, Michael I. Lewis, Steve C. Chen. 2010. Congenital and Developmental Lung Malformations. , 139-146.
CrossRef40
Mari Satoh, Keiko Aso, Tomotaka Nakayama, Kazuyuki Naoi, Satoshi Ikehara, Yumiko Uchino, Hiromitsu Shimada, Shinichi Takatsuki, Hiroyuki Matsuura, Tsutomu Saji. (2010) Autoimmune Thyroid Disease in Children and Adolescents With Idiopathic Pulmonary Arterial Hypertension. Circulation Journal 74:2, 371-374
CrossRef41
Ji-Yeon Sim. (2010) Nitric oxide and pulmonary hypertension. Korean Journal of Anesthesiology 58:1, 4
CrossRef42
Nazzareno Galiè, Marius M. Hoeper, Marc Humbert, Adam Torbicki, Jean-Luc Vachiery, Joan Albert Barberá, Maurice Beghetti, Paul Corris, Sean Gaine, J. Simon Gibbs, Miguel Ángel Gómez-Sánchez, Guillaume Jondeau, Walter Klepetko, Christian Opitz, Andrew Peacock, Lewis Rubin, Michael Zellweger, Gerald Simonneau. (2009) Guía de práctica clínica para el diagnóstico y tratamiento de la hipertensión pulmonar. Revista Española de Cardiología 62:12, 1464.e1-1464.e58
CrossRef43
, N. Galie, M. M. Hoeper, M. Humbert, A. Torbicki, J.-L. Vachiery, J. A. Barbera, M. Beghetti, P. Corris, S. Gaine, J. S. Gibbs, M. A. Gomez-Sanchez, G. Jondeau, W. Klepetko, C. Opitz, A. Peacock, L. Rubin, M. Zellweger, G. Simonneau, , A. Vahanian, A. Auricchio, J. Bax, C. Ceconi, V. Dean, G. Filippatos, C. Funck-Brentano, R. Hobbs, P. Kearney, T. McDonagh, K. McGregor, B. A. Popescu, Z. Reiner, U. Sechtem, P. A. Sirnes, M. Tendera, P. Vardas, P. Widimsky, , U. Sechtem, N. Al Attar, F. Andreotti, M. Aschermann, R. Asteggiano, R. Benza, R. Berger, D. Bonnet, M. Delcroix, L. Howard, A. N. Kitsiou, I. Lang, A. Maggioni, J. E. Nielsen-Kudsk, M. Park, P. Perrone-Filardi, S. Price, M. T. S. Domenech, A. Vonk-Noordegraaf, J. L. Zamorano. (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). European Heart Journal 30:20, 2493-2537
CrossRef44
Alisa Limsuwan, Pongsak Khowsathit. (2009) Assessment of pulmonary vasoreactivity in children with pulmonary hypertension. Current Opinion in Pediatrics 21:5, 594-599
CrossRef45
Shankar Baskar, Muralidhar Laxmanrao Kulkarni, Akhil Muralidhar Kulkarni, Suhasini Vittalrao, Preethi Muralidhar Kulkarni. (2009) Adams-Oliver syndrome: Additions to the clinical features and possible role of BMP pathway. American Journal of Medical Genetics Part A 149A:8, 1678-1684
CrossRef46
Hu Wang, Wen Li, Weili Zhang, Kai Sun, Xiaodong Song, Shuo Gao, Channa Zhang, Rutai Hui, Hong Hu. (2009) Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension. European Journal of Human Genetics 17:8, 1063-1069
CrossRef47
Fatima S Govani, Claire L Shovlin. (2009) Hereditary haemorrhagic telangiectasia: a clinical and scientific review. European Journal of Human Genetics 17:7, 860-871
CrossRef48
Nicholas W. Morrell, Serge Adnot, Stephen L. Archer, Jocelyn Dupuis, Peter Lloyd Jones, Margaret R. MacLean, Ivan F. McMurtry, Kurt R. Stenmark, Patricia A. Thistlethwaite, Norbert Weissmann, Jason X.-J. Yuan, E. Kenneth Weir. (2009) Cellular and Molecular Basis of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology 54:1, S20-S31
CrossRef49
Rajiv D. Machado, Oliver Eickelberg, C. Gregory Elliott, Mark W. Geraci, Masayuki Hanaoka, James E. Loyd, John H. Newman, John A. Phillips, Florent Soubrier, Richard C. Trembath, Wendy K. Chung. (2009) Genetics and Genomics of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology 54:1, S32-S42
CrossRef50
Gérald Simonneau, Ivan M. Robbins, Maurice Beghetti, Richard N. Channick, Marion Delcroix, Christopher P. Denton, C. Gregory Elliott, Sean P. Gaine, Mark T. Gladwin, Zhi-Cheng Jing, Michael J. Krowka, David Langleben, Norifumi Nakanishi, Rogério Souza. (2009) Updated Clinical Classification of Pulmonary Hypertension. Journal of the American College of Cardiology 54:1, S43-S54
CrossRef51
Pinar Yildiz. (2009) Molecular mechanisms of pulmonary hypertension. Clinica Chimica Acta 403:1-2, 9-16
CrossRef52
Vallerie V. McLaughlin, Stephen L. Archer, David B. Badesch, Robyn J. Barst, Harrison W. Farber, Jonathan R. Lindner, Michael A. Mathier, Michael D. McGoon, Myung H. Park, Robert S. Rosenson, Lewis J. Rubin, Victor F. Tapson, John Varga. (2009) ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. Journal of the American College of Cardiology 53:17, 1573-1619
CrossRef53
Wendy K. Chung, Liyong Deng, J. Sheila Carroll, Nicole Mallory, Beverly Diamond, Erika Berman Rosenzweig, Robyn J. Barst, Jane H. Morse. (2009) Polymorphism in the Angiotensin II Type 1 Receptor (AGTR1) is Associated With Age at Diagnosis in Pulmonary Arterial Hypertension. The Journal of Heart and Lung Transplantation 28:4, 373-379
CrossRef54
Sanjiv J. Shah. (2009) Genetics of systemic sclerosis-associated pulmonary arterial hypertension: Recent progress and current concepts. Current Rheumatology Reports 11:2, 89-96
CrossRef55
H. J. Durrington, N. W. Morrell. (2009) What we know and what we would like to know about genetics and pulmonary arterial hypertension. International Journal of Clinical Practice 63, 11-16
CrossRef56
M. D. McGoon, G. C. Kane. (2009) Pulmonary Hypertension: Diagnosis and Management. Mayo Clinic Proceedings 84:2, 191-207
CrossRef57
Gregory P. Star, Michele Giovinazzo, David Langleben. (2009) Effects of bone morphogenic proteins and transforming growth factor-beta on In-vitro production of endothelin-1 by human pulmonary microvascular endothelial cells. Vascular Pharmacology 50:1-2, 45-50
CrossRef58
Min Kim, Hwa Young Song, Hun Jeong, I Nae Park, Sang Bong Choi, Hyun Kyung Lee, Sung-Soon Lee, Young Min Lee, Su Young Kim, Yong Hoon Kim, Jin Won Huh. (2009) A Familial Case of Hereditary Hemorrhagic Telangiectasia. Tuberculosis and Respiratory Diseases 66:4, 314
CrossRef59
A. A. SHARATHKUMAR, A. SHAPIRO. (2008) Hereditary haemorrhagic telangiectasia. Haemophilia 14:6, 1269-1280
CrossRef60
Christina M. Rigelsky, Constance Jennings, Rainer Lehtonen, Omar A. Minai, Charis Eng, Micheala A. Aldred. (2008) BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. American Journal of Medical Genetics Part A 146A:19, 2551-2556
CrossRef61
Y Dempsie, M R MacLean. (2008) Pulmonary hypertension: therapeutic targets within the serotonin system. British Journal of Pharmacology 155:4, 455-462
CrossRef62
Marc Humbert. (2008) Mediators involved in HIV-related pulmonary arterial hypertension. AIDS 22:Suppl 3, S41-S47
CrossRef63
Michael M Lederman, Daniel Sereni, Gérald Simonneau, Norbert F Voelkel. (2008) Pulmonary arterial hypertension and its association with HIV infection: an overview. AIDS 22:Suppl 3, S1-S6
CrossRef64
Russell S. Tipps, Muhammed Mumtaz, Patrick Leahy, Brian W. Duncan. (2008) Gene array analysis of a rat model of pulmonary arteriovenous malformations after superior cavopulmonary anastomosis. The Journal of Thoracic and Cardiovascular Surgery 136:2, 283-289
CrossRef65
Maria J. Ruiz Cano, Pilar Escribano, Rocio Tello, Antonia Sanchez Nistal, Angela Flox, Juan F. Delgado. (2008) Different features of pulmonary hypertension in Rendu–Osler Syndrome. The Clinical Respiratory Journal 2:3, 191-192
CrossRef66
A. E. Ashley-Koch, L. Elliott, M. E. Kail, L. M. De Castro, J. Jonassaint, T. L. Jackson, J. Price, K. I. Ataga, M. C. Levesque, J. B. Weinberg, E. P. Orringer, A. Collins, J. M. Vance, M. J. Telen. (2008) Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease. Blood 111:12, 5721-5726
CrossRef67
Duk-Woo Park, Jong-Min Song, Ki-Hoon Han, Cheol Whan Lee, Duk-Hyun Kang, Sang-Do Lee, Suk-Jung Joo, Hyun Song, Jae Won Lee, Jae-Kwan Song. (2008) Different Gene Expression Patterns in the Lungs of Patients with Secondary Pulmonary Hypertension. Korean Circulation Journal 38:1, 51
CrossRef68
Masahito Sakuma, Jun Demachi, Jun Nawata, Jun Suzuki, Tohru Takahashi, Hiromi Matsubara, Satoshi Akagi, Kunio Shirato. (2008) Epoprostenol Infusion Therapy Changes Angiographic Findings of Pulmonary Arteries in Patients With Idiopathic Pulmonary Arterial Hypertension. Circulation Journal 72:7, 1147-1151
CrossRef69
Laura S. Inselman. 2008. Pulmonary Manifestations of Systemic Disorders. , 1053-1079.
CrossRef70
Stephen Y. Chan, Joseph Loscalzo. (2008) Pathogenic mechanisms of pulmonary arterial hypertension. Journal of Molecular and Cellular Cardiology 44:1, 14-30
CrossRef71
Eli Gabbay, Robert G. Weintraub, Lewis J. Rubin. 2008. Pulmonary Arterial Hypertension. , 759-771.
CrossRef72
Maya Fujiwara, Hisato Yagi, Rumiko Matsuoka, Kaoru Akimoto, Michiko Furutani, Shin-ichiro Imamura, Ritei Uehara, Tomotaka Nakayama, Atsuyoshi Takao, Makoto Nakazawa, Tsutomu Saji. (2008) Implications of Mutations of Activin Receptor-Like Kinase 1 Gene (ALK1) in Addition to Bone Morphogenetic Protein Receptor II Gene (BMPR2) in Children With Pulmonary Arterial Hypertension. Circulation Journal 72:1, 127-133
CrossRef73
Robert I. White. (2007) Pulmonary Arteriovenous Malformations: How Do I Embolize?. Techniques in Vascular and Interventional Radiology 10:4, 283-290
CrossRef74
Carla Olivieri, Fabio Pagella, Lucia Semino, Luca Lanzarini, Cristina Valacca, Andrea Pilotto, Sabrina Corno, Susi Scappaticci, Guido Manfredi, Elisabetta Buscarini, Cesare Danesino. (2007) Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. Journal of Human Genetics 52:10, 820-829
CrossRef75
Miguel A. Alejandre-Alcázar, Petar D. Shalamanov, Oana V. Amarie, Julia Sevilla-Pérez, Werner Seeger, Oliver Eickelberg, Rory E. Morty. (2007) Temporal and spatial regulation of bone morphogenetic protein signaling in late lung development. Developmental Dynamics 236:10, 2825-2835
CrossRef76
D. Liu, J. Wang, B. Kinzel, M. Mueller, X. Mao, R. Valdez, Y. Liu, E. Li. (2007) Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity. Blood 110:5, 1502-1510
CrossRef77
J POLLAK, R WHITEJR. (2007) Drs Pollak and White respond. Journal of Vascular and Interventional Radiology 18:7, 939-939
CrossRef78
Omar Ali, John Wharton, John Simon Russell Gibbs, Luke Howard, Martin Russell Wilkins. (2007) Emerging therapies for pulmonary arterial hypertension. Expert Opinion on Investigational Drugs 16:6, 803-818
CrossRef79
Albert Selva-O’Callaghan, Eva Balada, Silvia Serrano-Acedo, Carmen Pilar Simeon Aznar, Josep Ordi-Ros. (2007) Mutations of activin-receptor-like kinase 1 (ALK-1) are not found in patients with pulmonary hypertension and underlying connective tissue disease. Clinical Rheumatology 26:6, 947-949
CrossRef80
Friederike Gedge, Jamie McDonald, Amit Phansalkar, Lan-Szu Chou, Fernanda Calderon, Rong Mao, Elaine Lyon, Pinar Bayrak-Toydemir. (2007) Clinical and Analytical Sensitivities in Hereditary Hemorrhagic Telangiectasia Testing and a Report of de Novo Mutations. The Journal of Molecular Diagnostics 9:2, 258-265
CrossRef81
Darren B. Taichman, Jess Mandel. (2007) Epidemiology of Pulmonary Arterial Hypertension. Clinics in Chest Medicine 28:1, 1-22
CrossRef82
Terence K. Trow, John R. McArdle. (2007) Diagnosis of Pulmonary Arterial Hypertension. Clinics in Chest Medicine 28:1, 59-73
CrossRef83
Eric D. Austin, James E. Loyd. (2007) Genetics and Mediators in Pulmonary Arterial Hypertension. Clinics in Chest Medicine 28:1, 43-57
CrossRef84
Cabot, Richard C.Harris, Nancy Lee, Shepard, Jo-Anne O., Rosenberg, Eric S., Cort, Alice M., Ebeling, Sally H.Peters, Christine C., Boyer, Debra, Westra, Sjirk J., Kinane, T. Bernard, Stone, James R., . (2007) Case 3-2007. New England Journal of Medicine 356:4, 398-407
Full Text85
Seung Won Ra, Sang-Do Lee. (2007) Cellular and Molecular Pathophysiology of Idiopathic Pulmonary Arterial Hypertension. Tuberculosis and Respiratory Diseases 63:6, 475
CrossRef86
Vincent Cottin, Sophie Dupuis-Girod, Gaetan Lesca, Jean-François Cordier. (2007) Pulmonary Vascular Manifestations of Hereditary Hemorrhagic Telangiectasia (Rendu-Osler Disease). Respiration 74:4, 361-378
CrossRef87
Benjamin Sztrymf, Azzedine Yaïci, Barbara Girerd, Marc Humbert. (2007) Genes and Pulmonary Arterial Hypertension. Respiration 74:2, 123-132
CrossRef88
Andrea Donti, Roberto Formigari, Luca Ragni, Alessandra Manes, Nazzareno Galiè, Fernando M Picchio. (2007) Pulmonary arterial hypertension in the pediatric age. Journal of Cardiovascular Medicine 8:1, 72-77
CrossRef89
Ga??tan Lesca, Carla Olivieri, Nelly Burnichon, Fabio Pagella, Marie-France Carette, Brigitte Gilbert-Dussardier, Cyril Goizet, Joelle Roume, Muriel Rabilloud, Jean-Christophe Saurin, Vincent Cottin, Jerome Honnorat, Florence Coulet, Sophie Giraud, Alain Calender, Cesare Danesino, Elisabetta Buscarini, Henri Plauchu. (2007) Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network. Genetics in Medicine 9:1, 14-22
CrossRef90
Lewis J. Rubin. 2007. Pulmonary Hypertension: Thrombotic and Nonthrombotic in Origin. , 711-715.
CrossRef91
Judith Therrien, Sherryn Rambihar, Bill Newman, Kathy Siminovitch, David Langleben, Gary Webb, John Granton. (2006) Eisenmenger syndrome and atrial septal defect: Nature or nurture?. Canadian Journal of Cardiology 22:13, 1133-1136
CrossRef92
E. Vázquez Muñoz, J.J. Vázquez Rodríguez. (2006) Hipertensión pulmonar. Medicine - Programa de Formación Médica Continuada Acreditado 9:66, 4241-4247
CrossRef93
Federico Aucejo, Charles Miller, David Vogt, Bijan Eghtesad, Shunichi Nakagawa, James K. Stoller. (2006) Pulmonary hypertension after liver transplantation in patients with antecedent hepatopulmonary syndrome: A report of 2 cases and review of the literature. Liver Transplantation 12:8, 1278-1282
CrossRef94
Matthias Simon, Daniel Franke, Michael Ludwig, Ales F. Aliashkevich, Gertraud Köster, Johannes Oldenburg, Azize Boström, Andreas Ziegler, Johannes Schramm. (2006) Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. Journal of Neurosurgery 104:6, 945-949
CrossRef95
V. Cottin, A.-S. Blanchet, J.-F. Cordier. (2006) Manifestations vasculaires pulmonaires de la maladie de Rendu-Osler. Revue des Maladies Respiratoires 23:2, 53-66
CrossRef96
Pınar Bayrak-Toydemir, Jamie McDonald, Boaz Markewitz, Susan Lewin, Franklin Miller, Lan-Szu Chou, Friederike Gedge, Wei Tang, Hillary Coon, Rong Mao. (2006) Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations. American Journal of Medical Genetics Part A 140A:5, 463-470
CrossRef97
Haneen Sadick, Maliha Sadick, Karl Götte, Ramin Naim, Frank Riedel, Gregor Bran, Karl Hörmann. (2006) Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures. Wiener klinische Wochenschrift 118:3-4, 72-80
CrossRef98
L-E Wehner, BJ Folz, L Argyriou, S Twelkemeyer, U Teske, UW Geisthoff, JA Werner, W Engel, K Nayernia. (2006) Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clinical Genetics 69:3, 239-245
CrossRef99
Carla Olivieri, Lucav Lanzarini, Fabio Pagella, Lucia Semino, Sabrina Corno, Cristina Valacca, Henry Plauchu, Gaetan Lesca, Martine Barthelet, Elisabetta Buscarini, Cesare Danesino. (2006) Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genetics in Medicine 8:3, 183-190
CrossRef100
Rajiv D. Machado, Micheala A. Aldred, Victoria James, Rachel E. Harrison, Bhakti Patel, Edward C. Schwalbe, Ekkehard Gruenig, Bart Janssen, Rolf Koehler, Werner Seeger, Oliver Eickelberg, Horst Olschewski, C. Gregory Elliott, Eric Glissmeyer, John Carlquist, Miryoung Kim, Adam Torbicki, Anna Fijalkowska, Grzegorz Szewczyk, Jasmine Parma, Marc J. Abramowicz, Nazzareno Galie, Hiroko Morisaki, Shingo Kyotani, Norifumi Nakanishi, Takayuki Morisaki, Marc Humbert, Gerald Simonneau, Olivier Sitbon, Florent Soubrier, Florence Coulet, Nicholas W. Morrell, Richard C. Trembath. (2006) Mutations of the TGF-β type II receptorBMPR2 in pulmonary arterial hypertension. Human Mutation 27:2, 121-132
CrossRef101
Csaba Galambos, Jill Montgomery, Frank J. Jenkins. (2006) No Role for Kaposi Sarcoma-Associated Herpesvirus in Pediatric Idiopathic Pulmonary Hypertension. Pediatric Pulmonology 41:2, 122-125
CrossRef102
Akira UMEDA, Manabu TAGAWA, Takao KOHSAKA, Tomoo MIYAKAWA, Kazuteru KAWASAKI, Masayuki KITAMURA, Miwako NAKANO. (2006) Hepatopulmonary syndrome can show spontaneous resolution: Possible mechanism of portopulmonary hypertension overlap?. Respirology 11:1, 120-123
CrossRef103
Asrar Rashid, D. Dunbar Ivy. 2006. Pulmonary Hypertension in Children. , 274-287.
CrossRef104
Karen L. Swanson, Michael J. Krowka. 2006. Portopulmonary Hypertension. , 132-142.
CrossRef105
M. Fujimoto, M. Hasegawa, Y. Hamaguchi, K. Komura, T. Matsushita, K. Yanaba, M. Kodera, K. Takehara, S. Sato. (2006) A Clue for Telangiectasis in Systemic Sclerosis: Elevated Serum Soluble Endoglin Levels in Patients with the Limited Cutaneous Form of the Disease. Dermatology 213:2, 88-92
CrossRef106
C. Gregory Elliott. 2006. Genetics of Pulmonary Arterial Hypertension. , 50-65.
CrossRef107
Karl W. Thomas. 2006. Pulmonary Vascular Tumors and Malformations. , 210-236.
CrossRef108
Azad Raiesdana, Joseph Loscalzo. (2006) Pulmonary arterial hypertension. Annals of Medicine 38:2, 95-110
CrossRef109
Jennifer L. Snow, Peter Lloyd Jones, Darren B. Taichman. 2006. Pathobiologic Mechanisms of Pulmonary Arterial Hypertension. , 33-49.
CrossRef110
B. Sztrymf, A. Yaici, X. Jaïs, G. Simonneau, O. Sitbon, M. Humbert. (2005) Génétique de l’hypertension artérielle pulmonaire: données récentes et applications pratiques. Revue des Maladies Respiratoires 22:5, 796-805
CrossRef111
Michael W. Lamé, A. Daniel Jones, Dennis W. Wilson, H. J. Segall. (2005) Monocrotaline pyrrole targets proteins with and without cysteine residues in the cytosol and membranes of human pulmonary artery endothelial cells. PROTEOMICS 5:17, 4398-4413
CrossRef112
C. SABBÀ. (2005) A rare and misdiagnosed bleeding disorder: hereditary hemorrhagic telangiectasia. Journal of Thrombosis and Haemostasis 3:10, 2201-2210
CrossRef113
Justine H. Cohen, Marie E. Faughnan, Michelle Letarte, Kirk Vandezande, Shelley J. Kennedy, Murray D. Krahn. (2005) Cost comparison of genetic and clinical screening in families with hereditary hemorrhagic telangiectasia. American Journal of Medical Genetics Part A 137A:2, 153-160
CrossRef114
Ian Adatia. (2005) Improving the Outcome of Childhood Pulmonary Arterial Hypertension. Journal of the American College of Cardiology 46:4, 705-706
CrossRef115
O. Eickelberg, W. Seeger. (2005) Pulmonale Hypertonie. Der Internist 46:7, 759-768
CrossRef116
J.C. Caraballo Fonseca, C.D. Martínez Balzano, R. Sánchez de León. (2005) Disfunción endotelial en la hipertensión pulmonar. Archivos de Bronconeumología 41:7, 389-392
CrossRef117
F. Draghi, C. Olivieri, M. Precerutti, G.M. Danesino, F. Pagella, L. Lanzarini, L. Semino, C. Valacca, E. Buscarini, C. Danesino. (2005) Vascular abnormalities in the fingers of patients affected with hereditary hemorrhagic telangiectasia (HHT) as assessed by color doppler sonography. American Journal of Medical Genetics Part A 135A:1, 106-109
CrossRef118
(2005) Guías de Práctica Clínica sobre el diagnóstico y tratamiento de la hipertensión arterial pulmonar. Revista Española de Cardiología 58:5, 523-566
CrossRef119
Maria Luisa Fiorella, Douglas Ross, Katharine J. Henderson, Robert I. White. (2005) Outcome of Septal Dermoplasty in Patients With Hereditary Hemorrhagic Telangiectasia. The Laryngoscope 115:2, 301-305
CrossRef120
T. G. W. Letteboer, R. A. Zewald, E. J. Kamping, G. Haas, J. J. Mager, R. J. Snijder, D. Lindhout, F. A. M. Hennekam, C. J. J. Westermann, J. K. Ploos van Amstel. (2005) Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Human Genetics 116:1-2, 8-16
CrossRef121
K Brusgaard, AD Kjeldsen, L Poulsen, H Moss, P Vase, K Rasmussen, TA Kruse, M Hørder. (2004) Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clinical Genetics 66:6, 556-561
CrossRef122
Farber, Harrison W., Loscalzo, Joseph, . (2004) Pulmonary Arterial Hypertension. New England Journal of Medicine 351:16, 1655-1665
Full Text123
T. Satoh. (2004) Lack of circulating autoantibodies to bone morphogenetic protein receptor-II or activin receptor-like kinase 1 in mixed connective tissue disease patients with pulmonary arterial hypertension. Rheumatology 44:2, 192-196
CrossRef124
D. Montani, X. Jaïs, V. Ioos, O. Sitbon, G. Simonneau, M. Humbert. (2004) Traitement de l'hypertension artérielle pulmonaire. La Revue de Médecine Interne 25:10, 720-731
CrossRef125
Edmond G. Lemire, Patricia Petch. (2004) Short stature, pulmonary hypertension, sclerodactyly-like involvement and dysmorphic appearance: a newly described syndrome?. Clinical Dysmorphology 13:4, 227-230
CrossRef126
EKKEHARD GR??NIG, ROLF KOEHLER, GABRIEL MILTENBERGER-MILTENYI, RAINER ZIMMERMANN, MATTHIAS GORENFLO, DERLIZ MERELES, KARLIN ARNOLD, BARBARA NAUST, HEINRIKE WILKENS, ANDREAS BENZ, ALBRECHT VON HIPPEL, HERBERT E. ULMER, WOLFGANG K??BLER, HUGO A. KATUS, CLAUS R. BARTRAM, DIETMAR SCHRANZ, BART JANSSEN. (2004) Primary Pulmonary Hypertension in Children May Have a Different Genetic Background Than in Adults. Pediatric Research 56:4, 571-578
CrossRef127
Millan S. Patel, Glenn P. Taylor, Simi Bharya, Nouriya Al-Sanna'a, Ian Adatia, David Chitayat, M.E. Suzanne Lewis, Derek G. Human. (2004) Abnormal pericyte recruitment as a cause for pulmonary hypertension in Adams-Oliver syndrome. American Journal of Medical Genetics 129A:3, 294-299
CrossRef128
Mehran Mandegar, Yuan-Cheng B. Fung, Wei Huang, Carmelle V. Remillard, Lewis J. Rubin, Jason X.-J. Yuan. (2004) Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvascular Research 68:2, 75-103
CrossRef129
Pinar Bayrak-Toydemir, Rong Mao, Susan Lewin, Jamie McDonald. (2004) Hereditary hemorrhagic telangiectasia: An overview of diagnosis and management in the molecular era for clinicians. Genetics in Medicine 6:4, 175-191
CrossRef130
John H Newman, Richard C Trembath, Jane A Morse, Ekkehard Grunig, James E Loyd, Serge Adnot, Fabio Coccolo, Carlo Ventura, John A Phillips, James A Knowles, Bart Janssen, Oliver Eickelberg, Saadia Eddahibi, Phillipe Herve, William C Nichols, Gregory Elliott. (2004) Genetic basis of pulmonary arterial hypertension. Journal of the American College of Cardiology 43:12, S33-S39
CrossRef131
Marc Humbert, Nicholas W Morrell, Stephen L Archer, Kurt R Stenmark, Margaret R MacLean, Irene M Lang, Brian W Christman, E.Kenneth Weir, Oliver Eickelberg, Norbert F Voelkel, Marlene Rabinovitch. (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. Journal of the American College of Cardiology 43:12, S13-S24
CrossRef132
Gerald Simonneau, Nazzareno Galiè, Lewis J Rubin, David Langleben, Werner Seeger, Guido Domenighetti, Simon Gibbs, Didier Lebrec, Rudolf Speich, Maurice Beghetti, Stuart Rich, Alfred Fishman. (2004) Clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 43:12, S5-S12
CrossRef133
Marius M Hoeper, Michael J Krowka, Christian P Strassburg. (2004) Portopulmonary hypertension and hepatopulmonary syndrome. The Lancet 363:9419, 1461-1468
CrossRef134
Ga
tan Lesca, Henri Plauchu, Florence Coulet, Sylvain Lefebvre, Ghislaine Plessis, Sylvie Odent, Sophie Rivi
CrossRef135
Tim Higenbottam, Liz Laude, Celia Emery, Mohamed Essener. (2004) Pulmonary hypertension as a result of drug therapy. Clinics in Chest Medicine 25:1, 123-131
CrossRef136
Heike Varnholt, Richard Kradin. (2004) Pulmonary capillary hemangiomatosis arising in hereditary hemorrhagic telangiectasia. Human Pathology 35:2, 266-268
CrossRef137
Shoko Sugiyama, Hisao Hirota, Maki Yoshida, Yukiko Takemura, Yoshikazu Nakaoka, Yuichi Oshima, Kazuhiro Terai, Masahiro Izumi, Yasushi Fujio, Shinji Hasegawa, Toshiaki Mano, Yoshiaki Nakatsuchi, Masatsugu Hori, Keiko Yamauchi-Takihara, Ichiro Kawase. (2004) Novel Insertional Mutation in the Bone Morphogenetic Protein Receptor Type II Associated With Sporadic Primary Pulmonary Hypertension. Circulation Journal 68:6, 592-594
CrossRef138
H. Erhan Dincer, Kenneth W. Presberg. (2004) Current Management of Pulmonary Hypertension. Clinical Pulmonary Medicine 11:1, 40-53
CrossRef139
Gilbert Blaise, David Langleben, Bernard Hubert. (2003) Pulmonary Arterial Hypertension. Anesthesiology 99:6, 1415-1432
CrossRef140
Matthias Rindermann, Ekkehard Grünig, Albrecht von Hippel, Rolf Koehler, Gabriel Miltenberger-Miltenyi, Derliz Mereles, Karlin Arnold, Michael Pauciulo, William Nichols, Horst Olschewski, Marius M Hoeper, Jörg Winkler, Hugo A Katus, Wolfgang Kübler, Claus R Bartram, Bart Janssen. (2003) Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31. Journal of the American College of Cardiology 41:12, 2237-2244
CrossRef141
RICHARD C. TREMBATH AND, RACHEL HARRISON. (2003) Insights into the Genetic and Molecular Basis of Primary Pulmonary Hypertension. Pediatric Research 53:6, 883-888
CrossRef142
Filemon K Tan. (2003) Systemic sclerosis: the susceptible host (genetics and environment). Rheumatic Disease Clinics of North America 29:2, 211-237
CrossRef143
James R Runo, James E Loyd. (2003) Primary pulmonary hypertension. The Lancet 361:9368, 1533-1544
CrossRef144
Christopher P Denton, Carol M Black. (2003) Pulmonary hypertension in systemic sclerosis. Rheumatic Disease Clinics of North America 29:2, 335-349
CrossRef145
Kenneth W. Presberg, H. Erhan Dincer. (2003) Pathophysiology of pulmonary hypertension due to lung disease. Current Opinion in Pulmonary Medicine 9:2, 131-138
CrossRef146
Du, Lingling, Sullivan, Christopher C., Chu, Danny, Cho, Augustine J., Kido, Masakuni, Wolf, Paul L., Yuan, Jason X.-J., Deutsch, Reena, Jamieson, Stuart W., Thistlethwaite, Patricia A., . (2003) Signaling Molecules in Nonfamilial Pulmonary Hypertension. New England Journal of Medicine 348:6, 500-509
Full Text147
Anne M. Larson. (2003) Liver Disease in Hereditary Hemorrhagic Telangiectasia. Journal of Clinical Gastroenterology 36:2, 149-158
CrossRef148
Cecil David Bell. (2003) Endothelial cell tumors. Microscopy Research and Technique 60:2, 165-170
CrossRef149
Monty B. Tew, Frank C. Arnett, John D. Reveille, Filemon K. Tan. (2002) Mutations of bone morphogenetic protein receptor type II are not found in patients with pulmonary hypertension and underlying connective tissue diseases. Arthritis & Rheumatism 46:10, 2829-2830
CrossRef150
Ian Adatia. (2002) Recent advances in pulmonary vascular disease. Current Opinion in Pediatrics 14:3, 292-297
CrossRef151
Verne S. Caviness. (2002) Developmental vasculopathies as manifestations of dysregulated histogenetic signal transduction pathways. Current Opinion in Neurology 15:2, 127-131
CrossRef152
Newman, John H., . (2002) Treatment of Primary Pulmonary Hypertension — The Next Generation. New England Journal of Medicine 346:12, 933-935
Full Text153
Marlene Rabinovitch. (2001) Linking a serotonin transporter polymorphism to vascular smoothmuscle proliferation in patients with primary pulmonary hypertension. Journal of Clinical Investigation 108:8, 1109-1111
CrossRef154
Marc Humbert, Hilario Nunes, Olivier Sitbon, Florence Parent, Philippe Hervé, Gérald Simonneau. (2001) RISK FACTORS FOR PULMONARY ARTERIAL HYPERTENSION. Clinics in Chest Medicine 22:3, 459-475
CrossRef155
Loscalzo, Joseph, . (2001) Genetic Clues to the Cause of Primary Pulmonary Hypertension. New England Journal of Medicine 345:5, 367-371
Full Text156
Welch, Charles A., . (2001) Sacred Secrets — The Privacy of Medical Records. New England Journal of Medicine 345:5, 371-372
Full Text157
Tine L.M. De Backer, Jan-Peter Smedema, St??phane G. Carlier. (2001) Current Management of Primary Pulmonary Hypertension. BioDrugs 15:12, 801-817
CrossRef
