Colvin, L., Leonard, H., De Klerk, N.,Davis, M., Weaving, L., Williamson, S., & Christodoulou, J. (2004). Refining the phenotype of common mutations in Rett syndrome. Journal of Medical Genetics, 41, 25-30. Download snapshot, see article abstract.
Since Rett syndrome was first described, there has been much commentary about the range of expression of symptoms in Rett syndrome, including atypical forms of the condition. In 1999, mutations in the MECP2 gene were first associated with Rett syndrome. Since then, there has been considerable research examining the relationship between the expression of symptoms and type of MECP2 mutation.
Common types of mutations include missense mutations or truncating mutations. A gene can be pictured as a string of beads. A missense mutation is when a blue bead is put in place of a yellow bead. A truncating mutation is when the string of beads is cut short, resulting in a reduced number of beads (e.g 15 instead of 20). There are two types of mutations that can cause a truncation - nonsense mutations and frameshift mutations.
A nonsense mutation, is when the a bead is replaced by a "stop", similar to having a knot in a string of beads, and the string of beads is cut short. A frameshift mutation is where the beads follow a particular pattern and a bead is added in or taken out, causing a change in the pattern. Sometimes, this pattern change can also lead to a "stop" pattern, resulting in the string of beads being cut short.
All of these mutations in the gene can result in a protein that does not function the way it normally does, which can in turn, lead to a disease or illness. We investigated the differences in severity of symptoms between those with differentMECP2mutations.
What we did
We used information provided by families participating in the Australian Rett Syndrome database and coded this according to four severity scales. This allowed us to compare the severity of symptoms of girls and women in different groups.
We then grouped the girls and women according to the type of mutation they had and the location of their mutation. We also specifically examined the characteristics of those with the seven common mutations - p.R133C, p.T158M, p.R168X, p.R255X, p.R270X, p.R294X and p.R306C, compared to those with other mutations.
What we found
Overall, we found that those with truncating mutations had more severe symptoms and developed hand stereotypies at a younger age compared to those with other mutations. However those who had truncating mutations within the C-terminal region (located at the end of the gene) had much less severe symptoms when compared to those with similar mutations in other regions. We also found that mutations located in different functional domains of the MECP2 gene can result in different levels of symptom severity. This relates to the function of each domain in the MECP2 protein, with some domains appearing to have more functional importance then others.
When comparing specific mutations, we found that those with a p.R133C, p.R294X or a p.R306C mutation had the milder symptoms. On the other hand, those with a p.R270X mutation had more severe symptoms compared to those with other mutations. Those with a p.R168X mutation lost communication ability at an earlier age.
What does it mean
Those with certain mutations tended to have milder symptoms overall, whilst those with other mutations had more severe symptoms. It is important to understand the relationship between mutation type and the associated clinical features so doctors and families can prepare for the future needs of the child.