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Eur J Med Genet. 2018 Jan;61(1):11-16. doi: 10.1016/j.ejmg.2017.10.004. Epub 2017 Oct 9.

Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation.

Author information

1
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48103, USA.
2
Department of Pathology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
3
Department of Radiology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
4
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48103, USA. Electronic address: kingp@umich.edu.

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.

KEYWORDS:

Arteriovenous malformation; Capillary malformation; Endothelial cell; RASA1; Somatic mutation

PMID:
29024832
PMCID:
PMC5766414
DOI:
10.1016/j.ejmg.2017.10.004
[Indexed for MEDLINE]
Free PMC Article

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