Clinical Features and Mutations in the ENG, ACVRL1, and SMAD4 genes in Korean Patients with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.

[1]  F. Blanco,et al.  Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. , 2007, Journal of molecular biology.

[2]  V. Cottin,et al.  Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. , 2007, Medicine.

[3]  J. Honnorat,et al.  Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network , 2007, Genetics in Medicine.

[4]  P. Bayrak-Toydemir,et al.  A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7 , 2006, American journal of medical genetics. Part A.

[5]  A. Ganguly,et al.  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 , 2006, Human mutation.

[6]  D. Bouron‐Dal Soglio,et al.  Pulmonary arteriovenous malformation mimicking congenital cystic adenomatoid malformation in a newborn. , 2006, Journal of pediatric surgery.

[7]  R. Pyeritz,et al.  SMAD4 mutations found in unselected HHT patients , 2006, Journal of Medical Genetics.

[8]  P. Bayrak-Toydemir,et al.  Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations * , 2006, American journal of medical genetics. Part A.

[9]  K. Hörmann,et al.  Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures , 2006, Wiener klinische Wochenschrift.

[10]  D. Lindhout,et al.  Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia , 2005, Journal of Medical Genetics.

[11]  C. Shovlin,et al.  A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5 , 2005, Journal of Medical Genetics.

[12]  C. Schulte,et al.  High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients , 2005, Human mutation.

[13]  C. Sabbà,et al.  REVIEW ARTICLES: A rare and misdiagnosed bleeding disorder: hereditary hemorrhagic telangiectasia , 2005, Journal of thrombosis and haemostasis : JTH.

[14]  M. Letarte,et al.  Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease , 2005, Journal of Medical Genetics.

[15]  C. Sabb.  A rare and misdiagnosed bleeding disorder: hereditary hemorrhagic telangiectasia , 2005 .

[16]  S. Pinson,et al.  Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France , 2004, Human mutation.

[17]  A. Rustgi,et al.  A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4) , 2004, The Lancet.

[18]  T. Seki,et al.  Arterial Endothelium-Specific Activin Receptor-Like Kinase 1 Expression Suggests Its Role in Arterialization and Vascular Remodeling , 2003, Circulation research.

[19]  A. Guttmacher,et al.  Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations , 2003, Journal of medical genetics.

[20]  M. Letarte,et al.  Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia , 2003, Human mutation.

[21]  C. Westermann,et al.  The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro‐Caribbean population of the Netherlands Antilles: A family screening , 2003, American journal of medical genetics. Part A.

[22]  Liang‐Kung Chen,et al.  Hereditary hemorrhagic telangiectasia. , 2020, Zhonghua yi xue za zhi = Chinese medical journal; Free China ed.

[23]  K. Hörmann,et al.  Topical Estrogens Combined with Argon Plasma Coagulation in the Management of Epistaxis in Hereditary Hemorrhagic Telangiectasia , 2002, The Annals of otology, rhinology, and laryngology.

[24]  T. Shioya,et al.  Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan , 2002, Human mutation.

[25]  A. Guttmacher,et al.  Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). , 2000, American journal of medical genetics.

[26]  Robert I. White,et al.  Identification of Hereditary Hemorrhagic Telangiectasia Type 1 in Newborns by Protein Expression and Mutation Analysis of Endoglin , 2000, Pediatric Research.

[27]  A. Kjeldsen,et al.  Hereditary haemorrhagic telangiectasia: a population‐based study of prevalence and mortality in Danish patients , 1999, Journal of internal medicine.

[28]  J. Hughes.  Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia , 1998 .

[29]  J. Wrana,et al.  Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. , 1997, The Journal of clinical investigation.

[30]  C. Westermann,et al.  Epistaxis in hereditary haemorrhagic telangiectasia. , 1996, Rhinology.

[31]  D. W. Johnson,et al.  A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. , 1995, Genome research.

[32]  D. W. Johnson,et al.  Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1 , 1994, Nature Genetics.

[33]  K. Miyazono,et al.  Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. , 1993, Oncogene.

[34]  M. Porteous,et al.  Hereditary haemorrhagic telangiectasia: a clinical analysis. , 1992, Journal of medical genetics.

[35]  H. Plauchu,et al.  Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. , 1989, American journal of medical genetics.

[36]  W. H. Peery,et al.  Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). , 1987, The American journal of medicine.

[37]  A. Jacquard,et al.  [Genetic aspects of Rendu-Osler disease in Haut-Jura: convergence of methodological approaches of historic demography and medical genetics]. , 1980, Journal de genetique humaine.