WASHINGTON, D.C. -- Highlights of Nature Genetics FirstInternational Conference here last week included reports ongene therapy for cystic fibrosis; a genetic analysis of humanbreast cancer; similar bizarre patterns of gene mutation in twoneurological ailments, fragile X syndrome and Huntington'sdisease; and the latest on p53. During the rapid-fire conferencelast Thursday and Friday, researchers presented 40-minutetalks to an audience of about 300 people.
Ron Crystal, professor of medicine at Cornell University MedicalCollege and founder of a new Washington, D.C., gene therapycompany, GenVec, discussed the research foundations of thecompany's work.
"For many diseases, you can't take the cells out of the body inorder to perform gene therapy," Crystal said. "In my field, thelung, there is no way." Furthermore, he said, "One might be ableto avoid the cumbersome process of producing and purifyingthe gene."
Crystal has been developing adenovirus as the vector. Oneadvantage is it naturally infects many different cell types.Experiments in so-called cotton rats have been promising. Totreat cystic fibrosis, said Crystal, "we'd have to correctapproximately 5 to 10 percent of cells of the airway epithelia.We're getting more than 10 percent."
Protocols for human trials were approved by the RecombinantDNA Advisory Committee in December.
In the field of breast cancer, Mary-Claire King, a geneticist andepidemiologist in the school of public health at the Universityof California, Berkeley, said inherited breast cancer is the mostcommon genetic disease, with a risk of extraordinarysusceptibility of one in 150. King said her goal is to develop amolecular mammogram, and "it may not be too outrageous toimagine that one could reverse the altered phenotype if wecould identify the protein."
The overall risk for breast cancer rises to 10 percent by age 95,but a study of 1,500 families, which was recently published inthe American Journal of Human Genetics, suggested theexistence of a gene that would confer a very high -- 85 percent-- lifetime risk. The gene has been identified as brca1 onchromosome 17. It also appears to raise the risk of ovarian andprostate cancers.
This gene defect is present in about three women per 1,000,but its dominance results in the higher frequency ofsusceptibility.
Fragile X Syndrome
Stephen Warren, a biochemist at Emory University in Atlantadescribed a bizarre pattern of inheritance in fragile Xsyndrome, one of the most frequent causes of mentalretardation. The disorder afflicts one person in 850, regardlessof ethnic background. The protein produced by the gene isnecessary for normal brain function.
Twenty percent of those with the defect lack the disorder, andtransmission from carriers does not conform to Mendeliangenetics. Among male carriers, a low 9 percent of siblings areafflicted. But transmission to grandchildren through the motheris a high 40 percent.
When the gene was sequenced, researchers discovered theculprit: a multiply repeated trinucleotide. This is the site ofmost fragile X mutations. At low numbers of repeats -- a meanof around 30 -- phenotype is normal. Among carriers, the meanis about 84. Beyond 220 repeats, retardation is a virtualcertainty.
The repetitive sequence is unstable, often growing with a newgeneration, and the instability increases with the sequence'slength. Thus, the more repeats in a gene, the more likely thenumber of repeats will be greater in the next generation. Thisaccounts for the strange pattern of inheritance. But why thenumber of repeats grows remains a mystery.
In the larger sequences, methylation occurs in the repeat andpromoter region of the gene, preventing transcription.
The week before the conference, neurology (genetics) professorMarcy MacDonald of Harvard Medical School published thediscovery of the gene for Huntington's disease. Like fragile Xsyndrome, the genetics of Huntington's involves unstable,repetitive trinucleotides and non-Mendelian inheritance. But inthis case, either expansion or contraction can cause the disease.As with fragile X, researchers to not understand the cause ofthe instability.
Tomorrow: The genetics of cancer, Craig Venter stalks thegenome and more.
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.