CdLS SAC Awarded NIH Research Grant
May 2002

by Antonie Kline, M.D., Medical Director, CdLS-USA Foundation.

Great news! A four-year, $1 million grant from the National Institutes of Health (NIH) has been awarded to lan Krantz, M.D. [Clinical Geneticist, Children's Hospital of Philadelphia (CHOP), SAC member] for research on CdLS. Dr. Krantz, who will act as the principal investigator, told me that "this is the first NIH-funded grant specifically for CdLS." The grant will primarily fund ongoing molecular research in Dr. Krantz's laboratory that should uncover the elusive site(s) specifically causing the syndrome. Once this site has been identified, further research will be supported to look for the gene(s) which cause the syndrome, characterize it(them) molecularly, determine how the changes can produce a range of findings seen in CdLS and potentially lead to improved therapies and interventions for affected individuals. Dr. Krantz has selected a talented team of clinicians and researchers to help achieve these goals.

Currently, Dr. Krantz is studying the entire genome (the genetic makeup within all of us) to narrow down sites that look promising. His search is based on samples of families from around the world in which there is more than one family member affected with CdLS. Dr. Tom Strachan's group in the United Kingdom has focused its work on the long arm of chromosome 3 (3q) for a number of reasons, and is continuing to look at candidate genes in this region. Their group is also looking at several other regions that have been involved in rare chromosomal differences in some children with CdLS. Dr. Krantz's preliminary work suggests that other sites may be worth investigating. Two additional researchers, Marcella Devoto, Ph.D. and Donna Albertson, Ph.D. from A.I. DuPont Hospital in Wilmington, Delaware and the University of California in San Francisco respectively, will participate in the molecular search.

Laird Jackson, M.D. (Medical Geneticist and Director of CdLS SAC Worldwide) has also been involved with Dr. Krantz's research, particularly in the study of families with more than one affected member, and is another investigator on the grant. As Foundation veterans may know, he has single-handedly spearheaded research on CdLS since 1 987. Arthur Lander, M.D., Ph.D. (molecular researcher, SAC member), who works primarily in creating mouse models, is included on the grant as well. He intends to develop mouse models for the gene(s) once it(they) are discovered. Mouse models play a very important role in any current molecular research since mice have a genetic makeup close enough to humans to make them useful models for studying human disorders. Models offer a critical step in understanding the role a specific gene plays in development as well as facilitating study of potential therapeutic interventions.

Marc Hansen, Ph.D., a molecular researcher in Connecticut, has also been working on CdLS for the past several years and is another collaborator on the grant. He has been investigating several conditions that affect bone growth. At the International Conference last summer it was announced that he had identified a gene that appeared to be involved in CdLS. He has identified an expanded area on chromosome 3 that seems to be present in three copies in a few CdLS individuals, whereas control samples appear to have two copies. This area contains embryonic (very early in gestation) genes, which are important for human development, particularly the limbs. Unfortunately, since that announcement, although his work continues to look promising, the research has progressed slowly. Dr. Hansen told me that "there could be anywhere from six to twenty genes in this region of interest that could be significant. It's a matter of examining each gene in both cells and patient samples."

Another aspect of Dr. Krantz's grant is the start of a "diagnosis and management clinic" to be held several times a year at CHOP. Specialists in genetics, neurology, development, cardiology, ophthalmology, nephrology and/or urology, gastroenterology, as well as feeding and the gastrostomy tube teams will be available as needed. This two-day clinic will involve having interested families complete some paperwork, stay overnight in the Ronald McDonald House (not far from the hospital), and visit with appropriate professionals. Dr. Krantz is hiring a genetic counselor to help run this clinic and coordinate a comprehensive CdLS database. The clinic is in the final stages of planning and he hopes to have it in operation soon.

The last area that the grant covers is coordinating the formation of a database of clinical findings, and eventually, correlating this information with the molecular changes. This type of clinically-based research is called genotype-phenotype (gene changes and the effects) correlation. It involves identifying some significant changes molecularly and documenting any trends from the clinical point of view. I will also be participating in this aspect of the research.

This grant is a major step in enabling all of the research work on CdLS (initiated with support from the Joshua Ackles Fund and other private grants and donations) to continue. Congratulations to lan and his collaborators!