The gene for cystic fibrosis, the most common fatal geneticdisease in the U.S., has more than 300 known mutations, someof which affect the nature of the symptoms.
An article in today's issue of the journal Nature explores therelationship between three "missense" mutations and lesssevere forms of the disease. The article implies that some typesof cystic fibrosis may respond to different sorts of therapies,co-author Alan Smith, senior vice president for research atGenzyme Corp., told BioWorld. The Cambridge, Mass., company(NASDAQ:GENZ) has published three papers on the molecularbasis of the disease.
The research, carried out in collaboration with scientists led byMichael Welsh of the University of Iowa College of Medicine,found that an amino acid substitution in the cystic fibrosistransmembrane conductance regulator (CFTR) allowed theprotein to continue channeling chloride ions across the cellmembrane, but at a slower rate.
The variants were compared with normal CFTR in cultured ratthyroid epithelial cells, where the mutants showed 5 percent to30 percent of normal channeling of chloride ions, a componentof dissolved salt.
This channel regulates the movement of water and salt fromepithelial cells that envelop organs and may have other,unknown, functions. In cystic fibrosis, the transport of chlorideions is deficient. Patients experience gland dysfunction andmucous buildup in the lungs, which is conducive to infections.Half of patients die by age 29. The disease affects 30,000children and young adults in the U.S.
To help predict the outcome of the disease, Smith said, "we'rejust gradually going through the various mutations of thedisease and understanding the molecular basis." Some day, hesaid, physicians may be able to tell an infant's parents thenature and timing of symptoms they may expect in their child.
In most cases of cystic fibrosis, the CFTR fails to reach the rightplace in the membrane and cannot function, said study co-author David Sheppard of the University of Iowa. In the three"missense" mutations described in the Nature article, the CFTRhas minimal function. The substituted amino acids areapparently in locations that contribute to the chlorine channel"pore."
These mutations only affect about 2 percent of cystic fibrosispatients, but the study lends credence to the correlationbetween genetic variants and differences in the array ofsymptoms evident in a clinical evaluation.
"What we're saying is that even if you know the nature of thegene and the protein," Smith said, "there's still a wide spectrumof manifestations of the disease based on the exact nature ofthe mutation, and when you know this, you can think ofdifferent approaches to therapy, and they can be quite, quitedifferent."
For instance, the journal article concludes that these milderforms of cystic fibrosis, in which the CFTR mutants areapparently regulated normally, but transport less chloride ions,may respond to beta adrenergic agonists. These drugs increasecellular levels of the mediator cyclic-AMP and can be deliveredby inhalation. They are already used to dilate airways inasthmatics.
However, Smith believes rare versions of cystic fibrosis wouldmost likely be treated through broad measures such as genetherapy, which would "cure" the condition by introducing aproperly functioning CFTR gene into the patient's own cells.
The CFTR gene was identified four years ago, and its elucidationhas already affected diagnosis. Using screens based on the 20most frequent genetic types of cystic fibrosis, Genzyme'ssubsidiary IG Laboratories Inc. offers a "cheek brush" test oncells collected from the inside of the mouth that identifies up to85 percent of cystic fibrosis cases.
-- Nancy Garcia Assoicate Editor
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