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The Global Eye Spring 2008

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Mosaic RB1 Mutations

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Nadia Prigoda M.Sc, molecular biologist and Lab Technician at Retinoblastoma Solutions, puts mosaic RB1 mutations under the microscope.

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Mosaicism is thought to occur in approximately 10% of heritable retinoblastoma cases, but this phenomenon is not widely understood.  Here we take a look at mosaicism and its implications, and the genetic advances which are helping us help families learn more about how retinoblastoma may affect them An embryo starts out as one cell, generated as a result of fertilization of an egg with a sperm.  If either the egg or the sperm carries a mutation (genetic change) in the retinoblastoma (RB!) gene, then every cell of the

At work in the lab at Retinoblastoma Solutions

resulting embryo will carry the mutation, and the child will be highly likely to develop hereditary retinoblastoma. However, even if neither the egg nor the sperm carries an RB1 mutation, a change in the RB1 gene can still occur by chance, just after fertilization, while the embryo is still a single cell.  Again, the resulting embryo will have the mutation in every cell, and the child will be highly likely to develop hereditary retinoblastoma.  By contrast, if an RB1 mutation occurs in only one early retinal cell, and by chance a second RB1 mutation occurs in the same cell, then an isolated case of non-hereditary unilateral retinoblastoma is highly likely to develop. But what if this chance mutation happens in one cell during the development of the embryo?  For example, if the mutation occurs in one cell when the embryo is made of only eight cells, those 8 cells will divide to become 16 cells, two of which will have a mutated RB1 gene.  Those 16 cells divide to become 32, 4 of which have a mutant RB1 gene.  We would therefore expect about 13% of the resulting person’s cells to carry the mutation, and the rest to be normal. Such a mutation is not in all cells of the body, as is expected for an inherited case of retinoblastoma.  It is present in some cells and not others. The proportion of mutant cells may vary from one tissue to another.  This condition is called mosaicism.  The mosaics that you may be familiar with are created when small pieces of different materials (marble, tiles, or glass) are pieced together to make a picture.  In a similar way, a genetic mosaic is a whole organism made up of cells with different genotypes.  In order for a person with a mosaic RB1 mutation to have retinoblastoma, at least some cells of the retina must carry the RB1 mutation.  The earlier in embryonic development that a mosaic mutation occurs, the more likely that it will involve the cells that will later become the germ cells (eggs or sperm).  If germ cells are affected by the RB1 mutation, it is then possible to pass the mutation on to the patient’s offspring.  However, mosaicism itself cannot be inherited - If a child of a mosaic parent inherits the RB1 mutation, it will be present from conception, and will therefore be found in every cell of their body. Recent advances in genetic testing methods at Retinoblastoma Solutions have allowed us to detect certain RB1 mutations even if present in only one of every 100 cells of an individual.   For some RB1 mutations, mosaic mutations can only be detected when at least 25% of an individual’s cells carry the mutation.  Since blood samples are usually tested, we cannot usually tell which specific tissues carry the mutation, or how likely it is that the mutation will be in the reproductive tissues.  In one case we were able to test a sperm sample from an individual with retinoblastoma caused by a low level mosaic RB1 mutation detected in blood, and determined that his sperm sample did not show any sign of the RB1 mutation.  In another case, a woman whose blood sample showed a low level mosaic RB1 mutation had two children with retinoblastoma, each of whom carried the same mutation as their mother, in every cell of their body. Since only blood samples are usually tested and since the development of human embryos is not well understood, it is still not possible to accurately predict the risk for the children of a person with a mosaic RB1 mutation. We are currently working on developing a sensitive test able to detect low level mosaicism in other RB1 mutation types.  It is our hope that providing information on mosaicism will help us to better understand embryology, as well as the genetics of retinoblastoma and other cancers, and to provide families with more information to aid their medical care.

Retinoblastoma Solutions is a non-profit charitable company dedicated to advancing the care of families affected by retinoblastoma through provision of sensitive molecular genetic testing.  The lab also performs research to increase the power of its tests, and reduce their cost.

Visit the Rb Solutions website.

The Retinoblastoma Solutions team, during a forward planning retreat in April 2008.

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