Sometimes answers to medical problems come from unexpected places. This is especially true in the field of genetics, where investigations into specific diseases can lead to more general insights. Researchers studying a rare disease caused by inherited mutations in a gene discovered that non-inherited, also called somatic, mutations in the same gene can lead to the more common type of the same disease—sporadic venous malformations (VM). The study appeared in a recent issue of Nature Genetics.

VMs are abnormally formed blood vessels that can cause chronic pain and disfigurement. Depending on their size or their location near or on certain organs, they can also significantly impair function. VMs in the skin create bluish masses that can detract from a person's appearance. People with the inherited form of the disease typically have multiple small VMs on their bodies. People with the sporadic form of the disease generally have single, large VMs.

Researchers Nisha Limaye, Vinciane Wouters, and Miikka Vikkula of the de Duve Institute, Université catholique de Louvain, Brussels, Belgium led the study, which was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). They identified several mutations in the TEK gene, which codes for the endothelial cell tyrosine kinase receptor TIE2. The mutations lead to the dysfunction of the protein TIE2 in people with the sporadic form of the disease. Unlike the mutations of the inherited form of the disease, which are present in all cells of the body, the mutations for the somatic version of the disease only appear in VM tissue and are not passed down to children.

The researchers found eight unique somatic TEK mutations in VMs from 28 of 57 people with the sporadic form of the disease. Each mutation seems to inappropriately activate the TIE2 protein. The researchers also found that in four people, each carried two mutations in the TEK gene. In two of these people, the same pair of mutations were found in VMs at two different sites on the body. This leads the researchers to believe that the VMs have a shared origin in the development of the vascular system. This implies that the mutations occurred in affected endothelial cells or their progenitors, and that these are common in the multiple distinct VMs in the individual.

The researchers state that these findings may contribute to the development of therapies for VMs that target TIE2 protein pathways. In addition, this study may have far-reaching implications for investigations into other sporadic diseases that may share a common genetic origin with similar inherited diseases.

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Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, Eklund L, Boon LM, Vikkula M. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nature Genetics 2009 Jan 41(1):118-24. Epub 2008 Dec 14.