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Spectrum of Novel Hereditary Hemorrhagic Telangiectasia Variants in an Austrian Patient Cohort

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Objectives. Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disorder characterized by pathogenic blood vessel development and maintenance. HHT type 1 (HHT1) and type 2 (HHT2) are caused by variants in endoglin (ENG) and activin receptor-like kinase-1 (ACVRL1), respectively. The aim of this study was to identify the spectrum of pathogenic variants in ENG and ACVRL1 in Austrian HHT families. Methods. In this prospective study, eight Austrian HHT families were screened for variants in ENG and ACVRL1 by polymerase chain reaction amplification and sequencing of DNA isolated from peripheral blood. Results. Heterozygous variants were identified in all families under study. HHT1 was caused by a novel c.816+1G>A splice donor variant, a novel c.1479C>A nonsense (p.Cys493X) variant and a published c.1306C>T nonsense (p.Gln436X) variant in ENG. Variants found in ACVRL1 were novel c.200G>C (p.Arg67Pro) and known c.772G>A (p.Gly258Ser) missense variants in highly conserved residues, a known heterozygous c.100dupT frameshift (p.Cys34Leufs*4) and the known c.1204G>A missense (p.Gly402Ser) and c.1435C>T nonsense (p.Arg479X) variants as causes of HHT2. Conclusion. Novel and published variants in ENG (37.5%) and ACVRL1 (62.5%) were exclusively identified as the cause of HHT in an Austrian patient cohort. Identification of novel causative genetics variants should facilitate the development of tailored therapeutical applications in the future treatment of autosomal dominant HHT.

Abstract

Objectives. Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disorder characterized by pathogenic blood vessel development and maintenance. HHT type 1 (HHT1) and type 2 (HHT2) are caused by variants in endoglin (ENG) and activin receptor-like kinase-1 (ACVRL1), respectively. The aim of this study was to identify the spectrum of pathogenic variants in ENG and ACVRL1 in Austrian HHT families. Methods. In this prospective study, eight Austrian HHT families were screened for variants in ENG and ACVRL1 by polymerase chain reaction amplification and sequencing of DNA isolated from peripheral blood. Results. Heterozygous variants were identified in all families under study. HHT1 was caused by a novel c.816+1G>A splice donor variant, a novel c.1479C>A nonsense (p.Cys493X) variant and a published c.1306C>T nonsense (p.Gln436X) variant in ENG. Variants found in ACVRL1 were novel c.200G>C (p.Arg67Pro) and known c.772G>A (p.Gly258Ser) missense variants in highly conserved residues, a known heterozygous c.100dupT frameshift (p.Cys34Leufs*4) and the known c.1204G>A missense (p.Gly402Ser) and c.1435C>T nonsense (p.Arg479X) variants as causes of HHT2. Conclusion. Novel and published variants in ENG (37.5%) and ACVRL1 (62.5%) were exclusively identified as the cause of HHT in an Austrian patient cohort. Identification of novel causative genetics variants should facilitate the development of tailored therapeutical applications in the future treatment of autosomal dominant HHT.

참고문헌 (32)

  1. Schulte C, "High frequency of ENG and ALK1", ACVRL1 mutations in German HHT patients, 2005, pp.25(6), 595~
  2. "GeneReviews: hereditary hemorrhagic telangiectasia" (2000)[URL]
  3. Westermann CJ, "The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles : a family screening", Am J Med Genet A, 116(4), pp.324~328 (2003)
  4. 이승태, "Clinical Features and Mutations in the ENG, ACVRL1, and SMAD4 genes in Korean Patients with Hereditary Hemorrhagic Telangiectasia", Journal of Korean Medical Science, 24(1), pp.69~76 (2009), 대한의학회
  5. Shovlin CL, "Diagnostic criteria for hereditary hemorrhagic telangiectasia(Rendu-Osler-Weber syndrome)", Am J Med Genet, 91(1), pp.66~67 (2000)
  6. Abdalla SA, "Hereditary haemorrhagic telangiectasia : current views on genetics and mechanisms of disease", J Med Genet, 43(2), pp.97~110 (2006)
  7. Begbie ME, "Hereditary haemorrhagic telangiectasia(Osler-Weber-Rendu syndrome) : a view from the 21st century", Postgrad Med J, 79(927), pp.18~24 (2003)
  8. Sadick H, "Mutation analysis of"Endoglin"and"Activin receptor-like kinase"genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique", BMC Med Genet, 10, pp.53~ (2009)
  9. Letteboer TG, "Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia", J Med Genet, 43(4), pp.371~377 (2006)
  10. Bayrak-Toydemir P, "A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7", Am J Med Genet A, 140(20), pp.2155~2162 (2006)
  11. Cole SG, "A new locus for hereditary haemorrhagic telangiectasia(HHT3)maps to chromosome 5", J Med Genet, 42(7), pp.577~582 (2005)
  12. Gallione CJ, "A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4(SMAD4)", Lancet, 363(9412), pp.852~859 (2004)
  13. Mahmoud M, "Angiogenesis regulation by TGFβ signalling : clues from an inherited vascular disease", Biochem Soc Trans, 39(6), pp.1659~1666 (2011)
  14. Mahlawat P, "Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein(BMP)binding properties", Biochemistry, 51(32), pp.6328~6341 (2012)
  15. Townson SA, "Specificity and structure of a high affinity activin receptor-like kinase 1(ALK1)signaling complex", J Biol Chem, 287(33), pp.27313~27325 (2012)
  16. Alt A, "Structural and functional insights into endoglin ligand recognition and binding", PLoS One, 7(2), pp.e29948~ (2012)
  17. Llorca O, "Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia", J Mol Biol, 365(3), pp.694~705 (2007)
  18. Guerrero-Esteo M, "Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II", J Biol Chem, 277(32), pp.29197~29209 (2002)
  19. Hawinkels LJ, "Matrix metalloproteinase-14(MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis", Cancer Res, 70(10), pp.4141~4150 (2010)
  20. Venkatesha S, "Soluble endoglin contributes to the pathogenesis of preeclampsia", Nat Med, 12(6), pp.642~649 (2006)
  21. Letteboer TG, "Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients", Hum Genet, 116(1-2), pp.8~16 (2005)
  22. Lek M, "Analysis of protein-coding genetic variation in 60, 706 humans", Nature, 536(7616), pp.285~291 (2016)
  23. Lenato GM, "DHPLC-based mutation analysis of ENG and ALK-1genes in HHT Italian population", Hum Mutat, 27(2), pp.213~214 (2006)
  24. McDonald J, "Molecular diagnosis in hereditary hemorrhagic telangiectasia : findings in a series tested simultaneously by sequencing and deletion", duplication analysis, 2011, pp.79(4), 335~344
  25. Richards-Yutz J, "Update on molecular diagnosis of hereditary hemorrhagic telangiectasia", Hum Genet, 128(1), pp.61~77 (2010)
  26. Assis AM, "Three novel mutations in the activin receptor-like kinase 1(ALK-1)gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients", J Hum Genet, 52(3), pp.237~243 (2007)
  27. Abdalla SA, "Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia", Eur Respir J, 23(3), pp.373~377 (2004)
  28. Raab U, "Expression of normal and truncated forms of human endoglin", Biochem J, 339(Pt 3), pp.579~588 (1999)
  29. Berg JN, "The activin receptor-like kinase 1 gene : genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2", Am J Hum Genet, 61(1), pp.60~67 (1997)
  30. Olivieri C, "Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia", J Med Genet, 39(7), pp.E39~ (2002)
  31. Harrison RE, "Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia", J Med Genet, 40(12), pp.865~871 (2003)
  32. Pawlikowska L, "Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations", Stroke, 36(10), pp.2278~2280 (2005)

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