Genetic spotlight on a blood defect

The causes of defects in the blood system of newborn babies can be hard to establish if the errors are not inherited. An elegant approach has identified a gene that can encourage new blood vessels to grow.

Babies who are born with defects in their vascular system face serious medical and social problems. But we know little about the cause of these blood-vessel anomalies1,2. Discovering the genetic basis of such vascular birth defects remains a challenge, as most of these errors are not inherited. Instead, they occur sporadically and affect only certain areas of the body.

On page 640 of this issue, Tian et al.3 report the discovery of the first susceptibility gene for a disorder characterized by diverse defects in the vascular system — Klippel–Trenaunay syndrome (KTS). The authors show that when the gene, called VG5Q, is expressed at high levels, new blood vessels are stimulated to grow, suggesting that VG5Q is probably responsible for the vascular malformations seen in some patients with KTS. The unusual means by which Tian et al. identified and evaluated VG5Q, with a combination of human genetics and functional assays, underscores the importance of using similar approaches to identify other factors involved in the formation of new blood vessels (angiogenesis). Such factors could include molecules that are clinically relevant, or potential drug targets.

Blood vessels are lined by special endothelial cells and surrounded by smooth muscle cells. They are formed when founder endothelial cells give rise to a simple network of blood vessels — a ‘vascular plexus’— which is subsequently remodelled into a more mature network of large and small vessels2. This remodelling allows blood to carry oxygen to growing tissues, and so is essential for fetal development. If remodelling fails to occur normally, the vessels might become deformed, resulting in vascular birth defects. Unlike blood-vessel tumours, in which endothelial cells grow in excess, vessels in vascular malformations have normal numbers of endothelial cells but are improperly formed and remodelled. A few molecules, such as vascular endothelial growth factor and the protein Tie2, have been implicated in vascular birth defects1,4, but most vascular malformations remain unexplained in terms of the genes and molecules involved.

More than a century ago, the French physicians Maurice Klippel and Paul Trenaunay described (and gave their names to) a rare birth-defect syndrome that is characterized by malformations in the blood vessels of the skin, often occurring only in a single, enlarged limb5. Patients with KTS might, in fact, have a wide range of vessel defects in various parts of the body6. In most cases, it is the veins, rather than the arteries, that are affected. Superficial veins in the skin are often severely twisted and swollen, probably because the deeper network of veins hasn't formed properly. In other KTS patients, however, the basic fetal network of veins persists after birth at particular locations and fails to be remodelled into a more mature network. But other vessels, including the arteries, and more frequently the lymphatic vessels (which take fluid that has leaked out of the blood vessels back into the venous system), might also be affected. Such variation in symptoms strongly suggests that KTS is caused by different genes and by many factors. But until now, genetic links to the origin of KTS were entirely lacking.

Tian et al.3 turned to human genetics in their hunt for the molecules that cause KTS. One child with the syndrome was reported7 to have a chromosomal translocation — where a chromosome breaks and part of it fuses with another chromosome — between chromosomes 5 and 11. The authors found that chromosome 5 breaks within a certain region of the VG5Q gene (see Fig. 1). Although this region does not contain sequences that encode the VG5Q protein, it has some elements that regulate the expression of VG5Q. This means that when part of chromosome 11 is apposed to it, the expression of VG5Q increases.

Figure 1: Alterations in the VG5Q gene that lead to vascular defects in Klippel–Trenaunay syndrome.

a, As a result of a translocation between chromosomes 5 and 11, sequences of chromosome 11 become apposed to control sites in the VG5Q gene on chromosome 5. This increases the levels of the normal VG5Q protein — an angiogenic factor. b, An error in the coding sequence of VG5Q causes a mistake (E133K) in the protein. This mutant protein (mVG5Q) is thought to be hyperactive and therefore to increase angiogenic activity. Either mechanism increases susceptibility to the vascular defects typical of Klippel–Trenaunay syndrome.

But most KTS patients do not have this chromosomal translocation. In fact, Tian and colleagues found several patients who have a mutation in the coding region of the VG5Q gene. This results in substitution of one of the amino-acid constituents of the VG5Q protein by another — a glutamine (E) by a lysine (K). The mutation, known as E133K, changes the properties of the protein, and Tian et al. speculate that it becomes hyperactive (see Fig. 1). So increased expression of the normal version of VG5Q, or normal levels of the hyperactive version, could both cause blood-vessel defects consistent with KTS.

Besides the clinical link, what is the evidence that VG5Q actually affects angiogenesis, and how might it do so? Tian et al. used several methods to find more clues. First, although both endothelial and smooth muscle cells make the VG5Q protein, it mainly binds to and affects endothelial cells. Second, VG5Q promotes angiogenesis in chick embryos in vivo, whereas blocking its synthesis in cultured endothelial cells prevents them from forming vascular tubes. Third, the potentially hyperactive (E133K) version of VG5Q stimulates angiogenesis in vitro more strongly than does the normal protein. Finally, the angiogenic activity of VG5Q might, at least in part, be attributable to its interaction with TWEAK, a member of a family of proteins that also induce angiogenesis in vivo8. So there are data supporting a role for VG5Q in angiogenesis, although the precise molecular mechanisms involved require elucidation by more extensive in vivo experiments.

So is the mystery of the genetic basis for KTS solved? Certainly not. The chromosomal translocation has been found in only one affected child, and the E133K mutation is present in less than 4% of KTS patients. Many more KTS susceptibility genes are probably also involved. We do not know why the distribution of these blood-vessel defects is usually focal and varied, when all the patient's cells have the same genetic make-up. Perhaps variations in the VG5Q gene might not all be manifest, and only lead to vessel defects in particular tissues through other factors that have yet to be discovered. Alternatively, variation in the VG5Q gene might, by itself, be insufficient to produce defective vascular formation, but instead only increase the susceptibility of patients to develop KTS — that is, a second ‘hit’, a mutation of either the residual normal VG5Q gene or another gene, must then occur. As the latter mutation would not affect all the cells in the body, focal defects would develop only at particular locations9. This is not without precedent — a second hit in the gene for glomulin probably explains the focal nature of other vascular malformations1.

What are the overall implications of Tian and colleagues' findings3? First, they demonstrate the usefulness of genetic screening, which should prompt vascular biologists, clinicians and geneticists to consider similar strategies. Second, they show that mutations in VG5Q can disrupt angiogenesis in humans, which points to VG5Q as having the potential — hopefully, even a therapeutic one — to modulate angiogenesis.


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Lambrechts, D., Carmeliet, P. Genetic spotlight on a blood defect. Nature 427, 592–593 (2004).

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