» Research

Hunt goes on for gene clues


Dr Ian Krantz.

With Newcastle University and other CdLS researchers reporting that the search to find the gene is more frustrating than ever, Dr Ian Krantz, reports for Reaching Out on just what is involved in the search for the gene.

The goal of the many genetic research investigations going on around the world is to identify the underlying molecular cause of CdLS. Many people drive this process.

It involves the tireless work of Dr. Laird Jackson, the Foundation’s medical director; the research team of Dr.Tom Strachan at The University of Newcastle upon Tyne; and the staff at my research laboratory at The Children’s Hospital of Philadelphia.

Most importantly, it involves all of the children and adults with CdLS, and their families who have generously contributed samples.

When a sample is donated under informed consent, usually from the child/adult with CdLS as well as from their parents, it is sent to a research laboratory and is prepared in a number of ways.

From one tube we are able to isolate DNA directly. DNA is the basic building block that makes up all of the genes in our bodies.

By having a DNA sample on the individual with CdLS and on their parents we are able to search for, using molecular techniques, changes in genes that we think may be candidates for causing CdLS. By having a sample from the parents we are able to see if any changes found in the individual with CdLS is also present in the parents and if it is what we would term a disease-causing change.

Having these DNA samples also helps us to ask the question: Is there a particular region of DNA that is always present in children with CdLS and not in unaffected family members?

These type of studies are termed linkage analysis, as we are looking for regions of the genome (all of the DNA in an individual) that are “linked” with CdLS.

Families that have more than one affected child with CdLS are the most useful for these types of studies, simply because the more affected and unaffected family members there are, the more sure we can be of finding linked regions.

In addition to making DNA, a second tube of blood is usually drawn to establish a cell line. A cell line is created by taking the white blood cells out of the sample and preparing them in a way that allows them to continually divide and grow.

This allows us to have a renewable source of cells for future studies (i.e. to make more DNA), to look at the chromosomes (those structures that are visible under the microscope that are made up of DNA, and contain all the genes), and to have a source of cells to do specific functional studies once the CdLS gene has been found.

So where have we come in the last few years? We have been able to establish a collection of samples on over 100 individuals with CdLS and their family members.

We are in the process of performing high-resolution chromosome analysis on all individuals with CdLS, and have done so with over 30 samples to date. The reason for doing these analyses is to try to identify chromosomal abnormalities that may indicate regions where a candidate CdLS gene may be located.

To date we have not identified any chromosomal abnormalities amongst our samples. There have been a handful of chromosomal abnormalities identified in the past by other physicians.

The Newcastle team, headed by Dr. Tom Strachan are investigating several of these. They are looking for candidate genes at the sites of these rearrangements. Any chromosomal rearrangements identified in the Philadelphia lab are shared with Dr. Strachan’s group.

We have also collected skin samples on a number of CdLS individuals to look at the chromosomes in the skin cells called fibroblasts.

Some genetic disorders result from chromosomal differences that are not seen in the blood but are seen in other tissue samples such as the skin. We have not found any chromosomal abnormalities in the samples that we have examined.

Our labs are also in the process of looking at the chromosomes with different molecular techniques to specifically examine regions of the chromosomes at higher resolution than you can under the microscope.

The identification of the CdLS gene is our ultimate and attainable goal. The foundation has been laid, the path is clear. What we don’t know is if the identification of the CdLS gene will take years or months.

We are committed to moving the process ahead at full speed and relating the status of our research back to the families as quickly as possible.

The identification of this gene, or genes, will allow for a specific diagnostic test.

It will enable the development of a diagnostic test to confirm diagnosis, as well as assisting in counseling of families with regards to recurrence risk.

Through the identification of the CdLS gene(s) we will be able to study the role that it plays in human development and how it acts on a cellular level. Our true ultimate goal would be to develop better therapeutic

interventions for the children and adults with CdLS, through the identification of the CdLS gene, and by understanding its role in human development.
Reaching Out newsletter
July 2000