First Appeared Tuesday, 10 October '06

Researchers Discover Tiny Gene Mutations that Cause Birth Abnormalities

By Jeffrey Norris

The causes of developmental delay — what used to be known as mental retardation — are often unknown.

Environment often plays a role — think of fetal alcohol syndrome. But genes are just as important a cause, notes UCSF pediatrician and scientist Katherine Rauen, MD, PhD. In fact, the best known cause of developmental delay — Down syndrome — is genetic.

Down syndrome is the result of an abnormal duplication of all or most of an entire chromosome. The genetic defect is so large that for decades it has been detectible, even as myriad other genetic syndromes remain untraceable to this day. To diagnose Down syndrome, gene-bearing chromosomes -- in a preparation known as a karyotype -- are viewed under a microscope.

Katherine Rauen, MD, PhD

But unlike Down syndrome, many instances of developmental delay are due to small mutations in DNA. These small mutations often consist of no more than a single missing or substituted letter within the string of DNA alphabet building blocks that make up long sequences of genetic code.

Until recently, it was too difficult to track down such small genetic errors that are behind so many cases of developmental delay.

By using the latest “microarray” laboratory techniques — developed and refined by UCSF Comprehensive Cancer Center colleagues Donna Albertson and Daniel Pinkel — Rauen and her fellow genetic sleuths are succeeding at last in their searches.

Many of the syndromes these researchers investigate are rare. But when their numbers are combined, these disorders account for many thousands of cases of developmental delay in the United States alone.

Modern Gene Sleuthing

Rauen and her research colleagues used blood samples of 23 affected children to identify tiny genetic mutations responsible for cranio-facio-cutaneous (CFC) syndrome.

Children born with CFC syndrome have curly, brittle hair, skin conditions, slow growth — and most seriously — heart defects and major cognitive disabilities.

The blood samples became available thanks to the establishment of a blood bank by patient advocates — primarily parents. The advocates became aware of the scientific importance of tissue banks for tracking down the genetic causes of disease.

Rauen’s driving research interest is to explore how certain genes play a role both in normal development and in the development of cancers. She became interested in CFC syndrome after studying a similar developmental disorder — Costello syndrome — during her medical training. Costello syndrome and a third cause of developmental delay — Noonan syndrome — are caused by small mutations in genes that also are known to be involved in cancer.

DNA in this image is stained blue. Fluorescent dyes are used to probe sites where there are sub-microscopic deletions of DNA within chromosomes. Metaphase (replicated) chromosome pairs appear at the top of the image. The green dye is a marker for the chromosome of interest. The red dye — which highlights the DNA test probe — is absent from one of the green-labeled chromosome pairs — demonstrating that there is a DNA deletion on the chromosome and its copy. At the lower left, uncondensed, unreplicated DNA within a cell nucleus shows the same deletion.

Rauen’s research team discovered that CFC results from tiny miscodings in any of three different genes that relay signals within a cellular biochemical pathway called the MAPK pathway.

Mutations in the BRAF gene appeared to be responsible for 18 of the 23 cases of CFC. Three of the five remaining cases were due to mutations in two other genes — MEK1 or MEK2. These two genes encode proteins which act downstream from BRAF in the signaling pathway. The researchers later found that the two remaining cases also have BRAF mutations — ones rarely seen.

The CFC genes are different from those which cause Costello and Noonan syndromes. It now will be possible to clearly distinguish these syndromes with molecular tests.

Idea for Treatment

The MAPK signaling pathway plays a role in many cancers. However, it appears that there is not a large overlap between specific mutations associated with cancer and those that give rise to CFC. Rauen’s research team now is investigating the effects of specific mutations in cancerous and normal cells in the laboratory — to learn more about their physiological roles in both cancer and CFC.

Because the same misguided biochemical chain of events that causes CFC when mutations are inborn also contributes to cancer when it occurs later, there is hope that certain drugs under development to target cancer might also be used to limit the severity of CFC, Rauen says. Rauen’s team has launched preliminary laboratory studies to explore this idea.

" Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome " Pablo Rodriguez-Viciana, Osamu Tetsu, William E. Tidyman, Anne L. Estep, Brenda A. Conger, Molly Santa Cruz, Frank McCormick, Katherine A. Rauen Science 311(5675):1287-1290, 3 March 2006 Abstract | Full Text | Full Text (PDF)

Related Links:

Why Crawl When You Can Leap? Most cases of cardio-facial-cutaneous syndrome are caused by sporadic missense mutations in BRAF or MAP2K1/MAP2K2 — two transducers of MAPK signaling
Nature Reviews Genetics, March 2006