Medical College of Wisconsin
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Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genet 2018 Jan;61(1):11-16

Date

10/13/2017

Pubmed ID

29024832

Pubmed Central ID

PMC5766414

DOI

10.1016/j.ejmg.2017.10.004

Scopus ID

2-s2.0-85031325782 (requires institutional sign-in at Scopus site)   58 Citations

Abstract

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular disorder that is associated with inherited inactivating mutations of the RASA1 gene in the majority of cases. Characteristically, patients exhibit one or more focal cutaneous CM that may occur alone or together with AVM, arteriovenous fistulas or lymphatic vessel abnormalities. The focal nature and varying presentation of lesions has led to the hypothesis that somatic "second hit" inactivating mutations of RASA1 are necessary for disease development. In this study, we examined CM from four different CM-AVM patients for the presence of somatically acquired RASA1 mutations. All four patients were shown to possess inactivating heterozygous germline RASA1 mutations. In one of the patients, a somatic inactivating RASA1 mutation (c.1534C > T, p.Arg512*) was additionally identified in CM lesion tissue. The somatic RASA1 mutation was detected within endothelial cells specifically and was in trans with the germline RASA1 mutation. Together with the germline RASA1 mutation (c.2125C > T, p.Arg709*) in the same patient, the endothelial cell somatic RASA1 mutation likely contributed to lesion development. These studies provide the first clear evidence of the second hit model of CM-AVM pathogenesis.

Author List

Lapinski PE, Doosti A, Salato V, North P, Burrows PE, King PD

Author

Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Arteriovenous Malformations
Capillaries
Child
Endothelial Cells
Endothelium, Vascular
Female
Germ-Line Mutation
Humans
Male
Port-Wine Stain
p120 GTPase Activating Protein