Fragile What?

How many times have you got that response when talking to others about fragile X syndrome? Even we who are familiar with fragile X syndrome often feel that there is so much about it that we don’t understand. We are thus very fortunate to have Dr. Karen Usdin to help us out.

Dr. Usdin has spent the past 10 years studying fragile X syndrome in her laboratory at the NIH and for the past three years has served CFXF as a scientific Advisor. She has kindly agreed to explain, in very basic terms, the what, how, when, and why of fragile X. The series of articles she has written especially for us will be published in this and upcoming newsletters.

A Fragile X Primer,
by Karen Usdin

We are going to start off with an introduction to the human genome. You may already be familiar with this term from recent news reports about the completion of the Human Genome Sequencing project. Anyway, we can think of the genome as being like an encyclopedia containing all the information needed to make a human being. We can think of deoxyribonucleic acid or DNA as being the text of the encyclopedia. However unlike an encyclopedia written in English where 26 letters would be used to form words and sentences, the DNA “alphabet” is restricted to 4 letters or bases, known briefly as A, G, C and T.

The DNA text is divided into 46 volumes or chromosomes. Half of these volumes are inherited from our mothers, and half from our fathers. Twenty-two of the maternally inherited volumes have a corresponding volume that is paternally inherited. The remaining volumes correspond to the X and Y chromosomes. Females have 2 X chromosomes, 1 inherited from each parent. Males have 1 X chromosome, which is maternally inherited, and a Y chromosome, which is passed down from father to son. Information from only one X chromosome is used per cell, so in females one X chromosome needs to be switched off or inactivated. The imaginative name that scientists have come up with for this inactivation process is “X-inactivation”. The X chromosomes are usually inactivated randomly so that the maternal and paternal X chromosomes would each be used in about half of a woman’s cells.

Going back to our encyclopedia analogy, each volume or chromosome in the set contains a series of genes or chapters. Each gene is an instruction manual for the creation of a particular protein. Proteins are molecules that are directly involved in the day-to-day tasks of the cell. So for example, the protein hemoglobin is involved in transporting oxygen from the lungs to the rest of the body, while insulin, another protein, is involved in the regulation of blood sugar levels.

How does this discussion of genomes, chromosomes and genes relate to fragile X syndrome? Well, fragile X syndrome is caused by a problem in a single gene or chapter in our genome. This gene, known as fragile X mental retardation 1 or FMR1, is located on the X chromosome. Females, since they have 2 X chromosomes, have 2 versions or alleles of the FMR1 gene, one from each parent. In females with normal random X inactivation, the maternally inherited gene is active in ~50% of her cells, with the paternally inherited gene being active in the rest. This means that even if a female inherits a problematic FMR1 gene, its effects would only be felt in half of her cells. Since a male has only one copy of the gene, the effects would be felt in all of his cells. That is why boys are more likely to have more severe symptoms of fragile X syndrome than girls. For reasons that we don’t really understand, a small number of females show non-random or “skewed” X-inactivation where one chromosome is more likely to become inactivated than the other. If the chromosome with the affected FMR1 gene is the one that is more frequently inactivated, then the symptoms of fragile X syndrome are likely to be mild or even completely absent. In contrast, if the affected FMR1 gene is more frequently on the active X chromosome, then symptoms may be more severe.

In the next issue we will look at the FMR1 gene in more detail. We will cover the kind of changes that occur in the FMR1 gene. We will then get into what these changes mean for the way the gene is passed along, and for the different problems that these changes cause. In later issues we will get to (finally) what is known about the role of the protein coded for by the FMR1 gene. We will end off the series with a discussion of some new and exciting findings that might lead to useful treatments for some of the major symptoms of fragile X syndrome. If you have any questions or ideas for topics you would like to see covered in later installments please feel free to email me at: ku@helix.nih.gov.