Very Interesting CF Article

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Cystic Fibrosis Gene Mutations Missing From Some Cases A new study from s

Hopkins finds that some patients diagnosed with cystic fibrosis (CF) lack any

of the more than 1,000 reported disease-causing mutations in the only known

CF gene. Scheduled for presentation Oct. 18 at the annual meeting of the

American Society for Human Genetics in Baltimore, the findings also recently

appeared in the New England Journal of Medicine. The discovery may mean that

another gene, as yet unidentified, is to blame for these cases, or perhaps

these patients really have another, unknown disease, despite the similarity

of symptoms, the researchers suggest. Loss of the function of a protein

called CFTR was identified more than a decade ago as the cause of CF, a

life-shortening disease characterized by frequent, severe lung infections. In

less severe cases, known as " non-classic " CF, patients retain some working

CFTR, but not at normal levels. Over the years, scientists have linked these

conditions to more than 1,000 changes in the gene for CFTR. " Our findings

should lead to a discussion about what is, and is not, non-classic cystic

fibrosis, " says Garry Cutting, M.D., director of the DNA Diagnostic Lab at

the McKusick-s Institute of Genetic Medicine at Hopkins. " Hopefully,

extensive clinical evaluation of patients without identifiable changes in the

gene for CFTR will improve diagnosis and treatment of cystic fibrosis and

cystic fibrosis-like conditions. " In the new study, of 74 patients diagnosed

with non-classic CF and referred to the Cystic Fibrosis Foundation Genotyping

Center at Hopkins, detailed genetic analysis showed that 29 had mutations in

both copies of the CFTR gene, 15 had only a single mutation and 30 had no

detectable changes in their CFTR genes. (One copy is inherited from each

parent.) Cutting says other researchers now report the same observation.

" These patients were referred by physicians experienced with cystic fibrosis,

and we expected to find a causative mutation in each copy of each patient's

CFTR gene, " says Cutting, who also heads the genotyping center. " While it's

possible we could have missed some mutations, we believe they just weren't

there to be found in these patients. " The researchers looked for changes in

the CFTR gene in areas that carry instructions for the CFTR protein and those

that control the expression of the gene. It might be possible that changes to

the CFTR protein, unrelated to the sequence of its gene (so-called

" epigenetics " ), are at the root of these patients' conditions. To cause

disease, any changes must reduce or alter how the CFTR protein works. In

classic CF, there's no working CFTR protein, and a thick mucous forms that

traps bacteria in the airways, causing infections. In the non-classic

version, the theory held that some working CFTR protein remained to transport

charged atoms and water into and out of cells, while symptoms run the gamut

from mild to severe. First surprised that many patients lacked any mutations

in their CFTR genes, the scientists were surprised again when symptoms were

the same for these patients and those with one or two CFTR mutations. For

each measurement, including the standard test for CFTR function that measures

the amount of salt in sweat, each group looked like the others. " Once we saw

that we had a large number of patients without changes in CFTR, we thought

we'd be able to demonstrate that they had a different condition, " says

Cutting. " But we couldn't. " The Cystic Fibrosis Foundation Genotyping Center

at s Hopkins was launched in 1998 to look for genetic changes responsible

for cases of non-classic cystic fibrosis that couldn't be explained by the

most common known mutations. The Hopkins researchers are putting together a

detailed account of each patient's symptoms, biochemical and

electrophysiological measurements, genetic status, and possible non-genetic

contributors to find subtle differences between the groups that will allow

physicians to distinguish between conditions linked to CFTR mutations and

those that aren't. The study was funded by the Cystic Fibrosis Foundation and

the National Institutes of Health. Authors on the paper are Groman,

Meyer, Pamela Zeitlin, and Cutting, all of Hopkins; and

Wilmott, St. Louis University School of Medicine.

Becki

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