RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations.
BACKGROUND
Capillary malformation (CM), a common vascular abnormality, is often present among family members. Recently a rare form of hereditary vascular malformation termed capillary malformation-arteriovenous malformation (CM-AVM) was shown to be caused by heterozygous mutations in RASA1, encoding RAS p21 protein activator 1. CM-AVM is characterized by multiple, small CMs associated with either AVM or arteriovenous fistula (AVF) in affected individuals or at least one of their family members.


OBJECTIVE
The purpose of the study was to find out whether CMs in the absence of AVM/AVF are associated with RASA1 mutations.


METHODS
We assessed three families comprising 14 affected individuals with CMs. Linkage to the RASA1 locus was evaluated using microsatellite markers. The RASA1 gene was scrutinized for pathogenic mutations using denaturing high-performance liquid chromatography screening and direct sequencing.


RESULTS
AVM/AVF was identified in one of three affected families. CM without AVM/AVF was found to map in one large kindred to the RASA1 locus. Direct sequencing revealed novel heterozygous mutations segregating with CM in all three families. The mutations are predicted to result in premature termination of translation and RASA1 haplo-insufficiency.


CONCLUSIONS
We have demonstrated that the spectrum of clinical manifestations due to mutations in RASA1 is wider than previously thought and also includes typical CMs not associated with AVM/AVF.
Hershkovitz
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Laboratory of Molecular Dermatology, Department of Dermatology, Rambam Health Care Campus, P.O. Box 9602, Haifa 31096, Israel.
Bercovich
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D
Sprecher
E
E
Lapidot
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M
D000293:Adolescent; D002648:Child; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D019339:Port-Wine Stain / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020729:p120 GTPase Activating Protein / Q000235:genetics*
D020729:p120 GTPase Activating Protein