RASA1: variable phenotype with capillary and arteriovenous malformations

doi:10.1016/j.gde.2005.03.004

Current Opinion in Genetics & Development

Volume 15, Issue 3, June 2005, Pages 265-269

https://doi.org/10.1016/j.gde.2005.03.004 Get rights and content

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly discovered hereditary disorder. Its defining features are atypical cutaneous multifocal capillary malformations often in association with high-flow lesions: cutaneous, subcutaneous, intramuscular, intraosseous and cerebral arteriovenous malformations and arteriovenous fistulas. Some patients have Parkes Weber syndrome — a large congenital cutaneous vascular stain in an extremity, with bony and soft tissue hypertrophy and microscopic arteriovenous shunting. In the past, arteriovenous malformations and arteriovenous fistulas had been considered non-hereditary. A classical genetic approach was used to identify the locus. Candidate gene screening pinpointed mutations in RASA1 (p120-RASGAP) — a RasGTPase. RASA1 reverts active GTP-bound Ras into inactive GDP-bound form. Murine Rasa1 knockout and tetraploid-aggregated embryos with RNA interference exhibited abnormal vascular development. Lack of RASA1 activity caused inhibition of cell motility, possibly through p190-RhoGAP. Thus, RASA1 defects probably cause abnormal angiogenic remodeling of the primary capillary plexus that cannot be compensated for by other RasGAPs: RASA2, RASAL and NF1. Signaling pathways involving RASA1 might offer novel targets for treatment of high-flow vascular anomalies.

Introduction

Vascular malformations are localized developmental lesions that can involve any organ system but are most easily seen on the skin [1]. Although many vascular anomalies are harmless, others cause major functional problems or death. Vascular malformations are considered to be defects of angiogenic remodeling of the primary capillary plexus [2]. These lesions are divided into four major categories on the basis of clinical, rheological and histological and/or immunohistological features: capillary, lymphatic, venous and arteriovenous malformations [3].

Vascular malformations have several features of potential heuristic value. Most importantly, they are nearly always localized (i.e. the majority of vessels are normal and the malformed vessels arise in a limited area). Although the majority of vascular malformations do not seem to be inherited in a Mendelian way, numerous families with autosomal dominant inheritance have been reported [2]. Interestingly, sporadic lesions tend to be single and large whereas familial lesions are often small and multifocal [4^•]. Additionally, in the families with hereditary predisposition, there is wide clinical variability and high penetrance (around 90%). Expressivity varies from small harmless lesions to large symptomatic ones [4^•]. Moreover, it is the location of the lesion, rather than its size, that determines morbidity.

Genes for several vascular anomalies have been identified: TIE2 receptor tyrosine kinase for mucocutaneous venous malformation (VMCM; Online Mendelian Inheritance in Man (OMIM) 600195) [5]; glomulin for glomuvenous malformation (GVM; OMIM 138000) [6]; KRIT1 (Krev1 interaction trapped 1), malcavernin and programmed cell death 10 (PDC10) for cerebral cavernous malformation (CCM; OMIM 116860, 603284, 603285) [7, 8••, 9••]; endoglin and activin-like kinase for hereditary hemorrhagic telangiectasia (HHT; OMIM 187300, 600376) [10, 11]; and MADH4 for juvenile polyposis associated with HHT (JPHT; OMIM 175050) [12^•]. All mutations, except those in TIE2, are thought to cause loss of function. TIE2 mutations confer increased phosphorylation of the receptor and, thus, result in gain of function. All these mutations cause vascular defects that seem to be inherited as an autosomal dominant disorder. However, a somatic second-hit has been observed in the glomulin gene responsible for multiple GVMs, which suggests that paradominant inheritance (see Glossary) might explain their localized nature [2, 13]. Reports for CCMs do not support this mechanism [14, 15]; perhaps these lesions are caused by mutations in two different underlying genes (i.e. somatic transheterozygosity; see Glossary) (N Revencu and M Vikkula, unpublished).

CM-AVM is a similar, newly identified vascular disorder [16^••]. Here, we discuss its phenotypic variations, differential diagnosis and the molecular effects of the causative mutations on the function of RASA1.

Section snippets

Capillary malformation-arteriovenous malformation phenotype

The hallmark of CM-AVM is a small, round-to-oval, pink-red CM, typically multiple and in a haphazard distribution (Figure 1) [16••, 17•]. In the six identified families, 39 individuals carried a RASA1 mutation: four of them were unaffected, 25 had atypical CMs and 10 had a high-flow lesion in addition to the atypical CMs: two localized cutaneous and subcutaneous facial AVMs (one nasal and one frontal); one subcutaneous and intramuscular AVM of the foot; two extensive hemifacial AVMs with

Differential diagnosis

There are families reported to have hereditary benign telangiectasia (HBT) with CM-like lesions [18]. HBT consists of cutaneous telangiectasias similar to HHT, but without evolution of high-flow lesions in the lungs, brain or gastrointestinal tract. These telangiectasias are different from the more homogeneous capillary macules in CM-AVM. In addition, the telangiectasias in HBT are more often on the face, upper trunk and upper extremities and, in contrast to HHT, do not affect the mucosa,

RASA1

The germ line mutations reported in RASA1, on chromosome 5q13.1–14.3 (p120-RASGAP, OMIM 139150), cause premature termination codons (Figure 2) [16^••]. The earliest STOP is in the amino-terminal side of the known protein–protein interaction domains: the two SH2s, an SH3, a plekstrin homology domain and a protein kinase conserved region 2 [19, 20]. We have identified additional families with similar mutations (Revencu et al., unpublished). Thus, CM-AVM mutations are most likely to cause loss of

Conclusions

The identification of RASA1 mutations in a newly recognized disorder (CM-AVM) is an exciting discovery. The next steps include phenotypic delineation of the variable vascular phenotypes, including possible soft tissue and bony changes, and tumors; genotype–phenotype correlating studies; clinical follow up of genetically defined patients for prevalence of bleeding, tumors and so on; testing the paradominant inheritance model; and identification of possible signaling pathways that could be

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We are grateful to all patients and family members for their invaluable contributions. These studies were partially supported by Interuniversity Attraction Poles initiated by the Belgian Science Policy network 5/25, Concerted Research Actions — Convention n°02/07-276 of the Belgian French Community Ministry, the Integrated Project (LSHG-CT-2004-503573) of the European Commission's Sixth Framework Programme, and the FNRS (Fonds National de la Recherche Scientifique) (to MV, a ‘Maître de

Glossary

Doppler: A method of ultrasonography to measure flow.
Hemiparesis: One-sided paralysis.
Paradominant inheritance: Pathology caused by the combination of a germ line and a postzygotic mutation.
Sequelae: The secondary alterations caused by a lesion.
Somatic transheterozygosity: Somatic mutation in paradominant inheritance occurs in different sites of the same gene or in a gene other than the one with a germ line mutation.
Vascular steal: High-flow with direct arterio-venous shunting, without passage through

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View full text

RASA1: variable phenotype with capillary and arteriovenous malformations

Introduction

Section snippets

Capillary malformation-arteriovenous malformation phenotype

Differential diagnosis

RASA1

Conclusions

References and recommended reading

Acknowledgements

Glossary

Am J Hum Genet

Nat Genet

Am J Hum Genet

Nat Genet

Am J Med Genet

Cell

J Cell Biol

Mol Cell Biol

Vascular Birthmarks: Hemangiomas and Malformations

Vascular malformations: localized defects in vascular morphogenesis

Clin Genet

Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics

Plast Reconstr Surg

Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities

Arch Dermatol

Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2

Cell

Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations

Am J Hum Genet

Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1

Nat Genet

A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)

Lancet

Four common glomulin mutations cause two-thirds of glomuvenous malformations (“familial glomangiomas”): evidence for a founder effect

J Med Genet

CCM1 mutation screen of sporadic cases with cerebral cavernous malformations

Neurology