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. 1999 Jul;65(1):125–133. doi: 10.1086/302450

A gene for inherited cutaneous venous anomalies ("glomangiomas") localizes to chromosome 1p21-22.

L M Boon 1, P Brouillard 1, A Irrthum 1, L Karttunen 1, M L Warman 1, R Rudolph 1, J B Mulliken 1, B R Olsen 1, M Vikkula 1
PMCID: PMC1378082  PMID: 10364524

Abstract

Venous malformations (VMs) are localized defects of vascular morphogenesis. They can occur in every organ system, most commonly in skin and muscle. They can cause pain and bleeding, and in some critical locations they can be life threatening. Usually venous anomalies occur sporadically, but families with dominant inheritance have been identified. Using linkage analysis, we have established in earlier reports that some families with inherited VMs show linkage to chromosome 9p21; the mutation causes ligand-independent activation of an endothelial cell-specific receptor tyrosine kinase, TIE-2. Here we show that VMs with glomus cells (known as "glomangiomas"), inherited as an autosomal dominant trait in five families, are not linked to 9p21 but, instead, link to a new locus, on 1p21-p22, called "VMGLOM" (LOD score 12.70 at recombination fraction.00). We exclude three known positional candidate genes, DR1 (depressor of transcription 1), TGFBR3 (transforming growth factor-beta receptor, type 3), and TFA (tissue factor). We hypothesize that cutaneous venous anomalies (i.e., glomangiomas) are caused by mutations in a novel gene that may act to regulate angiogenesis, in concert with the TIE-2 signaling pathway.

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Selected References

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  1. Allikmets R., Shroyer N. F., Singh N., Seddon J. M., Lewis R. A., Bernstein P. S., Peiffer A., Zabriskie N. A., Li Y., Hutchinson A. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805–1807. doi: 10.1126/science.277.5333.1805. [DOI] [PubMed] [Google Scholar]
  2. Boon L. M., Mulliken J. B., Vikkula M., Watkins H., Seidman J., Olsen B. R., Warman M. L. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet. 1994 Sep;3(9):1583–1587. doi: 10.1093/hmg/3.9.1583. [DOI] [PubMed] [Google Scholar]
  3. Bugge T. H., Xiao Q., Kombrinck K. W., Flick M. J., Holmbäck K., Danton M. J., Colbert M. C., Witte D. P., Fujikawa K., Davie E. W. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6258–6263. doi: 10.1073/pnas.93.13.6258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cheung A. H., Stewart R. J., Marsden P. A. Endothelial Tie2/Tek ligands angiopoietin-1 (ANGPT1) and angiopoietin-2 (ANGPT2): regional localization of the human genes to 8q22.3-q23 and 8p23. Genomics. 1998 Mar 15;48(3):389–391. doi: 10.1006/geno.1997.5207. [DOI] [PubMed] [Google Scholar]
  5. Davis S., Aldrich T. H., Jones P. F., Acheson A., Compton D. L., Jain V., Ryan T. E., Bruno J., Radziejewski C., Maisonpierre P. C. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996 Dec 27;87(7):1161–1169. doi: 10.1016/s0092-8674(00)81812-7. [DOI] [PubMed] [Google Scholar]
  6. GORLIN R. J., FUSARO R. M., BENTON J. W. Multiple glomus tumor of the pseudocavernous hemangioma type; report of case manifesting a dominant inheritance pattern. Arch Dermatol. 1960 Nov;82:776–778. doi: 10.1001/archderm.1960.01580050118018. [DOI] [PubMed] [Google Scholar]
  7. Goodman T. F., Abele D. C. Multiple glomus tumors. A clinical and electron microscopic study. Arch Dermatol. 1971 Jan;103(1):11–23. doi: 10.1001/archderm.103.1.11. [DOI] [PubMed] [Google Scholar]
  8. Huang L., Turck C. W., Rao P., Peters K. G. GRB2 and SH-PTP2: potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase. Oncogene. 1995 Nov 16;11(10):2097–2103. [PubMed] [Google Scholar]
  9. Iqbal A., Cormack G. C., Scerri G. Hereditary multiple glomangiomas. Br J Plast Surg. 1998 Jan;51(1):32–37. doi: 10.1054/bjps.1997.0116. [DOI] [PubMed] [Google Scholar]
  10. Johnson D. W., Berg J. N., Baldwin M. A., Gallione C. J., Marondel I., Yoon S. J., Stenzel T. T., Speer M., Pericak-Vance M. A., Diamond A. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996 Jun;13(2):189–195. doi: 10.1038/ng0696-189. [DOI] [PubMed] [Google Scholar]
  11. Jones N., Dumont D. J. The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene. 1998 Sep 3;17(9):1097–1108. doi: 10.1038/sj.onc.1202115. [DOI] [PubMed] [Google Scholar]
  12. Kontos C. D., Stauffer T. P., Yang W. P., York J. D., Huang L., Blanar M. A., Meyer T., Peters K. G. Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol Cell Biol. 1998 Jul;18(7):4131–4140. doi: 10.1128/mcb.18.7.4131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Korpelainen E. I., Kärkkäinen M., Gunji Y., Vikkula M., Alitalo K. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene. 1999 Jan 7;18(1):1–8. doi: 10.1038/sj.onc.1202288. [DOI] [PubMed] [Google Scholar]
  14. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Maisonpierre P. C., Suri C., Jones P. F., Bartunkova S., Wiegand S. J., Radziejewski C., Compton D., McClain J., Aldrich T. H., Papadopoulos N. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55–60. doi: 10.1126/science.277.5322.55. [DOI] [PubMed] [Google Scholar]
  16. McAllister K. A., Grogg K. M., Johnson D. W., Gallione C. J., Baldwin M. A., Jackson C. E., Helmbold E. A., Markel D. S., McKinnon W. C., Murrell J. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994 Dec;8(4):345–351. doi: 10.1038/ng1294-345. [DOI] [PubMed] [Google Scholar]
  17. Meister A. The gamma-glutamyl cycle. Diseases associated with specific enzyme deficiencies. Ann Intern Med. 1974 Aug;81(2):247–253. doi: 10.7326/0003-4819-81-2-247. [DOI] [PubMed] [Google Scholar]
  18. Rozet J. M., Gerber S., Perrault I., Camuzat A., Calvas P., Viegas-Pequignot E., Molina-Gomes D., Le Paslier D., Chumakov I., Munnich A. Structure and physical mapping of DR1, a TATA-binding protein-associated phosphoprotein gene, to chromosome 1p22.1 and its exclusion in Stargardt disease (STGD). Genomics. 1996 Sep 15;36(3):554–556. doi: 10.1006/geno.1996.0508. [DOI] [PubMed] [Google Scholar]
  19. Rudolph R. Familial multiple glomangiomas. Ann Plast Surg. 1993 Feb;30(2):183–185. doi: 10.1097/00000637-199302000-00017. [DOI] [PubMed] [Google Scholar]
  20. Sato T. N., Tozawa Y., Deutsch U., Wolburg-Buchholz K., Fujiwara Y., Gendron-Maguire M., Gridley T., Wolburg H., Risau W., Qin Y. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995 Jul 6;376(6535):70–74. doi: 10.1038/376070a0. [DOI] [PubMed] [Google Scholar]
  21. Stratmann A., Risau W., Plate K. H. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol. 1998 Nov;153(5):1459–1466. doi: 10.1016/S0002-9440(10)65733-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Suri C., Jones P. F., Patan S., Bartunkova S., Maisonpierre P. C., Davis S., Sato T. N., Yancopoulos G. D. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996 Dec 27;87(7):1171–1180. doi: 10.1016/s0092-8674(00)81813-9. [DOI] [PubMed] [Google Scholar]
  23. Toomey J. R., Kratzer K. E., Lasky N. M., Stanton J. J., Broze G. J., Jr Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood. 1996 Sep 1;88(5):1583–1587. [PubMed] [Google Scholar]
  24. Valenzuela D. M., Griffiths J. A., Rojas J., Aldrich T. H., Jones P. F., Zhou H., McClain J., Copeland N. G., Gilbert D. J., Jenkins N. A. Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1904–1909. doi: 10.1073/pnas.96.5.1904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vikkula M., Boon L. M., Carraway K. L., 3rd, Calvert J. T., Diamonti A. J., Goumnerov B., Pasyk K. A., Marchuk D. A., Warman M. L., Cantley L. C. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181–1190. doi: 10.1016/s0092-8674(00)81814-0. [DOI] [PubMed] [Google Scholar]
  26. Vikkula M., Boon L. M., Mulliken J. B., Olsen B. R. Molecular basis of vascular anomalies. Trends Cardiovasc Med. 1998 Oct;8(7):281–292. doi: 10.1016/s1050-1738(98)00024-3. [DOI] [PubMed] [Google Scholar]
  27. Vikkula M., Mariman E. C., Lui V. C., Zhidkova N. I., Tiller G. E., Goldring M. B., van Beersum S. E., de Waal Malefijt M. C., van den Hoogen F. H., Ropers H. H. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell. 1995 Feb 10;80(3):431–437. doi: 10.1016/0092-8674(95)90493-x. [DOI] [PubMed] [Google Scholar]
  28. Witzenbichler B., Maisonpierre P. C., Jones P., Yancopoulos G. D., Isner J. M. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem. 1998 Jul 17;273(29):18514–18521. doi: 10.1074/jbc.273.29.18514. [DOI] [PubMed] [Google Scholar]

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