Lymphangiogenomics

The basic aim of our research is to get insights into the molecular mechanisms behind certain human diseases, and especially to evaluate the importance of genetic variation in disease development. For many disorders, the cause is unknown, and therefore current treatments are aimed at alleviating symptoms. Identification of the primary causes as well as the modulating factors would allow to develop treatments that are more “curative” and more specific. To this end, we use a genetic approach. We are interested in disorders affecting the vascular system, the blood and lymphatic vessels:

1. Venous malformations, glomuvenous malformations (“glomangiomas”) and Maffucci syndrome

2. Lymphedema

3. Vascular anomalies affecting capillaries (hemangiomas, capillary malformation, cerebral cavernous

     malformation, telangiectasia, capillary malformation/arterio-venous malformation)

As this research is based on human DNA extracted from blood and tissue samples obtained from patients, the group works tightly together with several clinicians and multidiciplinary centers worldwide (e.g. Centre des Malformations Vasculaires, Cliniques Universitaires St-Luc; Vascular Anomalies Center, Children’s Hospital, Boston, USA, Consultation des Angiomes, Hôpital Lariboisière, Paris.

Responsible for this project:

Dr. Miikka Vikkula

Christian de Duve Institute of Cellular Pathology

BCHM/Laboratory of Human Molecular Genetics

P.O. Box UCL 75.39 (Avenue Hippocrate 74)

1200 Brussels, Belgium

Phone: +32 2 764 7496

Fax: +32 2 764 7460

E-mail: vikkula@bchm.ucl.ac.be

Homepage: http://www.icp.ucl.ac.be/vikkula

Relevant publications:

Selected papers on lymphedema:

1. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensen MAM, Vikkula M. Mutations in the transcription factor SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72:1470-1478, 2003.

2. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 67:295-301, 2000.

Selected papers on vascular anomalies:

1. Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, Eklund L, Boon LM, Vikkula M. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet. 41(1):118-24, 2009.
    

2. Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, Clapuyt, Hammer F, Dubois J, Baselga E, Brancati F, Carder R, Ceballos Quintal JM, Dallapiccola B, Fischer G, Frieden IJ, Garzon M, Harper J, Johnson-Patel J, Labrèze C, Martorell L, Paltiel H, Pohl A, Prendiville J, Quere I, Siegel DH, Valente EM, van Hagen A, van Hest L, Vaux KK, Vicente A, Weibel L, Chitayat D, Vikkula M. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies and specific neural tumors associated with RASA1 mutations. Hum Mutat. in press.
    

3. Brouillard P and Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. 2007
    

4. Vikkula M, Karkkainen MJ, Alitalo K. Editors Epstein CJ, Erickson RP, Wynshaw-Boris A. Angiopoietins, TIEs, Ephrins, VEGFs and VEGFRs. In : Inborn errors of development: the molecular basis of clinical disorders on morphogenesis. Oxford University Press, New York, NY., 987-996, 2004.
    

5. Eerola I, Boon LM, Mulliken JB, Burrows PE, Vanwijck R, Vikkula M. Capillary Malformation-Arteriovenous Malformation, a heretofore undescribed clinical and genetic entity, is caused by RASA1 mutations. Am J Hum Genet 73:1240-1249, 2003.
    

6. Brouillard P, Vikkula M. Vascular malformations: localized defects in vascular morphogenesis. Clinical Genetics 63: 340-351, 2003.
    

7. Eerola I, Boon LM, Watanabe S, Grynberg H, Mulliken JB, Vikkula M. Locus for susceptibility for familial capillary malformation ("port-wine stain") maps to 5q. Eur J Hum Genet 10:375-380, 2002.
    

8. Vikkula M. An update on molecular basis of vascular malformations. In: Benigne Gefäßfehl- und Neubildungen der Haut (Benign vascular malformations and tumors). Authors: Michael Landthaler, Ulrich Hohenleutner and Thomas Vogt, Editor Blackwell Verlag GmbH, Berlin, Germany, 15-24, 2002.
    

9. Brouillard P, Boon LM, Mulliken JB, Ghassibé M, Warman ML, Tan OT, Olsen BR, Vikkula M. Mutations in a novel factor glomulin are responsible for glomuvenous malformations (“glomangiomas”). Am J Hum Genet 70:866-874, 2002.
    

10. Karttunen L, Felbor U, Vikkula M, Olsen BR, Zon L, ed. Vascular matrix and disorders. In: Hematopoiesis: A Developmental Approach. Oxford University Press, New York, NY, 784-795, 2001.
     

11. Vikkula M, Boon L, Mulliken JB. Molecular genetics of vascular malformation. Invited Mini-Review for Matrix Biology 20:327-335, 2001.
     

12. Eerola I, McIntyre BAS, Vikkula M. Identification of eight novel 5'-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1. Biochimica et Biophysica Acta - Gene Structure and Expression 1517:464-467, 2001.
     

13. Irrthum A, Brouillard P, Boon LM, Warman ML, Olsen BR, Mulliken JB, Enjolras O, Vikkula M. Linkage disequilibrium narrows locus for venous malformations with glomus cells (VMGLOM) to a single YAC of 1.48 Mbp. Eur J Hum Genet 9:34-38, 2001.
     

14. Brouillard P, Olsen BR, Vikkula M. High resolution physical and transcript map of the locus for venous malformations with "glomus" cells (VMGLOM) on chromosome 1p21-22. Genomics 67:96-101, 2000.
     

15. Eerola I, Plate KH, Spiegel R, Boon LM, Mulliken JB, Vikkula M. KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation. Hum Mol Genet 9:1351-1355, 2000.
     

16. Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, Rudolph R, Mulliken JB, Olsen BR, Vikkula M. A gene for inherited cutaneous venous anomalies ("glomangiomas") localizes to chromosome 1p21-22. Am J Hum Genet 65:125-133, 1999.
     

17. Karttunen L, Vikkula M, Boon LM, Olsen BR.TIE-2 signalling and venous malformations. In: Angiogenesis in health and disease: basic mechanisms and clinical applications. Editor Gabor M. Rubanyi, ed., Marcel Dekker Inc. New York, NY, 89-96, 1999.
     

18. Vikkula M, Boon LM, Carraway III KL, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE-2. Cell 87:1181-1190, 1996