Rapid genetic disease screening possible using laser mass spectrometry
In 1993, using their new ability to detect 35 to 110 base pairs in a single DNA strand,
Winston Chen and his associates at ORNL were the first to demonstrate the use of laser
desorption mass spectrometry (LDMS) to detect a mutant gene responsible for cystic
fibrosis (CF). Their demonstration used clinical samples custom prepared by Drs. Karla
Matteson and Lan-Yang Chang, both of the University of Tennessee Medical Center
CF is an inherited, fatal disease in which mucus buildup promotes digestive disorders
and bacterial infections in the lungs. Because each person with CF is the child of
parents who both carry defective forms (alleles) of a particular gene, there is interest in
large-scale screening to let people know their chances of having a child with CF.
"Our technique could be used to rapidly screen many people for a specific defect in a
gene on chromosome 7 that causes 70% of all CF cases," Chen says. "The defect is the
absence of three base pairs of DNA in both alleles that control production of CFTR, a
protein that prevents mucus buildup. CF carriers have a single defective allele that may
be passed on to their offspring, and people born with CF have two defective alleles.
The ORNL group was the first to show that LDMS can diagnose a genetic disease via
DNA analysis. The technique, which is not yet used commercially, screens for CF in
minutes, not hours, making it 10 times faster than conventional gel electrophoresis.
Also, it does not use toxic chemicals or radioactive materials, which require costly
methods of disposal.
In their continuing collaboration with Drs. Matteson and Nick Potter, also of UTMC,
Chen and his colleagues demonstrated in 1996 that a single-base mutation (replacement
of the right base with the wrong one) can be detected by LDMS.
More recently, he and Dr. Potter showed that LDMS can detect neurodegenerative
diseases that result from dynamic mutations, such as Huntingdon Disease. The normal
Huntingdon gene has 9 to 24 repeats of the GAC sequence. The mutant gene causing
Huntingdon disease has more than 25 repeats. The researchers showed that LDMS can
identify the HD gene because of its greater molecular weight, resulting from the many
"Laser desorption mass spectrometry," says Chen, "is emerging as a new tool for
screening populations for various genetic diseases."