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Archives of Dermatological Research

, Volume 300, Issue 7, pp 385–388 | Cite as

A novel mutation in RASA1 causes capillary malformation and limb enlargement

  • Dov Hershkovitz
  • Reuven Bergman
  • Eli Sprecher
Short Communication

Abstract

Capillary malformations are common vascular malformations. Several syndromes have been described in which CMs are present in association with limb enlargement, among these are Klippel–Trenaunay syndrome (KTS) and Parkes Weber syndrome (PWS). Mutations in the RASA1 gene have been shown to underlie the capillary malformation–arterio-venous malformation (CM–AVM) syndrome, sometimes presenting with PWS. We identified a family comprising a patient with CMs and limb enlargement and a number of family members with CM/CM–AVM. A novel mutation in RASA1 was found to underlie the disease in this case. The present results illustrate the extensive degree of phenotypic heterogeneity associated with deleterious mutations in RASA1.

Keywords

Capillary malformation RASA1 Parkes Weber syndrome Klippel–Trenaunay syndrome 

Notes

Acknowledgments

We are grateful to the family members for their participation in our study. We wish to thank Rita Fuhrer-Mor and Vered Friedman for services in nucleic acid analysis.

References

  1. 1.
    Brouillard P, Vikkula M (2003) Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340–351PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen MM Jr (2006) Vascular update: morphogenesis, tumors, malformations, and molecular dimensions. Am J Med Genet A 140:2013–2038PubMedGoogle Scholar
  3. 3.
    Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73:1240–1249PubMedCrossRefGoogle Scholar
  4. 4.
    Friedman E, Gejman PV, Martin GA, McCormick F (1993) Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nat Genet 5:242–247PubMedCrossRefGoogle Scholar
  5. 5.
    Garzon MC, Huang JT, Enjolras O, Frieden IJ (2007) Vascular malformations. Part II: associated syndromes. J Am Acad Dermatol 56:541–564PubMedCrossRefGoogle Scholar
  6. 6.
    Garzon MC, Huang JT, Enjolras O, Frieden IJ (2007) Vascular malformations: part I. J Am Acad Dermatol 56:353–370, quiz 371–354PubMedCrossRefGoogle Scholar
  7. 7.
    Glanzer JG, Liao L, Baker T, McMullen MH, Langan AS, Crandall LZ, Vorce RL (2002) Organization and regulation of the human rasGAP gene. Gene 285:149–156PubMedCrossRefGoogle Scholar
  8. 8.
    Gutierrez S, Magano L, Delicado A, Mori MA, de Torres ML, Fernandez L, Palomares M, Fernandez E, Tarduchy GR, Molano J, Gracia R, Pajares IL, Lapunzina P (2006) The G397A (E133K) change in the AGGF1 (VG5Q) gene is a single nucleotide polymorphism in the Spanish population. Am J Med Genet A 140:2832–2833PubMedGoogle Scholar
  9. 9.
    Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, Shih TS, Jacks T, Pawson T (1995) Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 377:695–701PubMedCrossRefGoogle Scholar
  10. 10.
    Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P (1998) Klippel–Trenaunay syndrome: spectrum and management. Mayo Clin Proc 73:28–36PubMedCrossRefGoogle Scholar
  11. 11.
    Jacobs AH, Walton RG (1976) The incidence of birthmarks in the neonate. Pediatrics 58:218–222PubMedGoogle Scholar
  12. 12.
    Kulkarni SV, Gish G, van der Geer P, Henkemeyer M, Pawson T (2000) Role of p120 Ras-GAP in directed cell movement. J Cell Biol 149:457–470PubMedCrossRefGoogle Scholar
  13. 13.
    Kunath T, Gish G, Lickert H, Jones N, Pawson T, Rossant J (2003) Transgenic RNA interference in ES cell-derived embryos recapitulates a genetic null phenotype. Nat Biotechnol 21:559–561PubMedCrossRefGoogle Scholar
  14. 14.
    Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, Chen Q, Szafranski P, Rao S, Wu L, Housman DE, DiCorleto PE, Driscoll DJ, Borrow J, Wang Q (2004) Identification of an angiogenic factor that when mutated causes susceptibility to Klippel–Trenaunay syndrome. Nature 427:640–645PubMedCrossRefGoogle Scholar
  15. 15.
    Trahey M, McCormick F (1987) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–545PubMedCrossRefGoogle Scholar
  16. 16.
    Trahey M, Wong G, Halenbeck R, Rubinfeld B, Martin GA, Ladner M, Long CM, Crosier WJ, Watt K, Koths K et al (1988) Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242:1697–1700PubMedCrossRefGoogle Scholar
  17. 17.
    Whelan AJ, Watson MS, Porter FD, Steiner RD (1995) Klippel–Trenaunay–Weber syndrome associated with a 5:11 balanced translocation. Am J Med Genet 59:492–494PubMedCrossRefGoogle Scholar
  18. 18.
    Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E (1983) The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140:5–12PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Dov Hershkovitz
    • 1
    • 2
    • 3
  • Reuven Bergman
    • 1
    • 2
  • Eli Sprecher
    • 1
    • 2
    • 3
  1. 1.Department of Dermatology and Laboratory of Molecular DermatologyRambam Health Care CampusHaifaIsrael
  2. 2.Faculty of MedicineTechnion, Israel Institute of TechnologyHaifaIsrael
  3. 3.Center for Translational Genetics, Rappaport Institute for Research in the Medical SciencesTechnion, Israel Institute of TechnologyHaifaIsrael

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