Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant bleeding disorder and has two variants, HHT1 and HHT2, associated with mutations in the ENG and ALK-1 genes, respectively. We identified one Chinese HHT2 family to investigate the pathogenic gene and its possible mechanism of action by mutation screening and functional study. One substitution mutation (1717C>T) in exon 10 of the ALK-1 was found by sequencing of all exons of ENG and ALK-1 and caused a R479X mutation in the ALK-1 protein. ALK-1 mRNA and plasma thrombomodulin were measured by real-time quantitative PCR and ELISA, respectively. There was no significant difference in the expression levels of ALK-1 mRNA between patients and healthy individuals. A significantly higher level of thrombomodulin was found in HHT patients. These findings indicate that the mutation causes truncation of the ALK-1 protein at the post-transcriptional level; the plasma thrombomodulin may provide an easy diagnostic indicator in HHT patients.
Get full access to this article
View all access options for this article.
References
1.
Azuma H -2000-. Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia. J Med Invest47:81–90.
2.
Boehme MW, Autschbach F, Zuna I, Scherbaum WA, Stange E, Raeth U, et al. -1997-. Elevated serum levels and reduced immunohistochemical expression of thrombomodulin in active ulcerative colitis. Gastroenterology113:107–117.
3.
Boffa MC, Karmochkine M -1998-. Thrombomodulin: an overview and potential implications in vascular disorders. Lupus7-Suppl 2-:S120–S125.
4.
Bourdeau A, Dumont DJ, Letarte M -1999-. A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest104:1343–1351.
5.
Braverman IM, Keh A, Jacobson BS -1990-. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol95:422–427.
6.
Dittman WA -1991-. Thrombomodulin: biology and potential cardiovascular applications. Trends Cardiovasc Med1:331–336.
7.
Esmon CT -1995-. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J9:946–955.
8.
Gorlin RJ, Cohen MM Jr, Levin LS -1990-. Syndromes of the head and neck. 3rd ed. New York: Oxford University Press.
9.
Jessurun GA, Kamphuis DJ, van der Zande FH, Nossent JC -1993-. Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations. Clin Neurol Neurosurg95:193–198.
10.
Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, et al. -1996-. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet13:189–195.
11.
Kjeldsen AD, Brusgaard K, Poulsen L, Kruse T, Rasmussen K, Green A, et al. -2001-. Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families. Am J Med Genet98:298–302.
12.
Lathrop GM, Lalouel JM -1984-. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet36:460–465.
13.
Lux A, Attisano L, Marchuk DA -1999-. Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. J Biol Chem274:9984–9992.
14.
Magriples U, Hsu CD, Chan DW, Nickless N, Copel JA -1997-. Circulating thrombomodulin levels and clinical correlates in pregnant diabetics. Am J Perinatol14:605–608.
15.
Miller SA, Dykes DD, Polesky HF -1988-. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res16:1215.
16.
Ohji T, Urano H, Shirahata A, Yamagishi M, Higashi K, Gotoh S, et al. -1995-. Transforming growth factor beta 1 and beta 2 induce down-modulation of thrombomodulin in human umbilical vein endothelial cells. Thromb Haemost73:812–818.
17.
Osler W -1901-. On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Bull Johns Hopkins Hosp12:333–337.
18.
Pau H, Carney AS, Walker R, Murty GE -2000-. Is oestrogen therapy justified in the treatment of hereditary haemorrhagic telangiectasia: a biochemical evaluation. Clin Otolaryngol Allied Sci25:547–550.
19.
Piantanida M, Buscarini E, Dellavecchia C, Minelli A, Rossi A, Buscarini L, et al. -1996-. Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2. J Med Genet33:441–443.
20.
Plauchu H, Bideau A -1984-. Epidemiologie et constitution d’un registre de population à propos d’une concentration géographique d’une maladie héréditaire rare. Popul4–5:765–786.
21.
Porteous ME, Burn J, Proctor SJ -1992-. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet29:527–530.
22.
Richter KK, Fink LM, Hughes BM, Sung CC, Hauer-Jensen M -1997-. Is the loss of endothelial thrombomodulin involved in the mechanism of chronicity in late radiation enteropathy? Radiother Oncol44:65–71.
23.
Sandusky G, Berg DT, Richardson MA, Myers L, Grinnell BW -2002-. Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads. J Biol Chem277:49815–49819.
24.
Shimizu H, Julius MA, Giarre M, Zheng Z, Brown AM, Kitajewski J -1997-. Transformation by Wnt family proteins correlates with regulation of beta-catenin. Cell Growth Differ8:1349–1358.
25.
Shovlin CL, Hughes JM, Scott J, Seidman CE, Seidman JG -1997-. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet61:68–79.
26.
Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. -2000-. Diagnostic criteria for hereditary hemorrhagic telangiectasia -Rendu-Osler-Weber syndrome-. Am J Med Genet91:66–67.
27.
Su JL -1999-. Hereditary hemorrhagic telangiectasia: a family with seven patients. Clinic Stomatol15:246–246 -in Chinese-.
28.
van der Driesche S, Mummery CL, Westermann CJ -2003-. Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovasc Res58:20–31.
29.
Wallace GM, Shovlin CL -2000-. A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1. Thorax55:685–690.
30.
Zhang GS, Yi Y, Peng HL, Shen JK, Xie DH, He XB -2004-. Clinical phenotypes, ALK1 gene mutation and level of related plasma proteins in Chinese hereditary hemorrhagic telangiectasia. Chin Med J -Engl-117:808–812.
