Genetic Disease Only Partially to Blame for Expected Disorder

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Genetic Disease Only Partially to Blame for Expected Disorder

Thursday, July 22, 1999

[From EureAlert: http://www.eurekalert.org/releases/unncmed-gmn072199.html ]

CHAPEL HILL - Gene mutations tied to inherited diseases may cause only

a portion of the expected disorder, according to scientists at the

University of North Carolina at Chapel Hill.

That such " minor mutations " can cause unexpected effects stems largely

from recent findings in cystic fibrosis (CF).

Writing in the July issue of Clinical Chemistry, Dr. Lawrence M.

Silverman, professor of pathology and laboratory medicine at UNC-CH School

of Medicine and Dr. J. Friedman, a postdoctoral research associate,

note that mutations in CFTR - the CF gene - can cause several distinct

conditions having clinical similarities to CF.

" And when we look at people with ICP and CBAVD, we find mutations in

the same gene - the CF gene. So it's the type of mutation within the gene

itself that causes the specific disease manifestations, " he states.

Silverman and Friedman argue that atypical disease manifestations

caused by minor mutations in the CF gene may have important implications for

genetic screening and the field of molecular diagnostics in general.

At the annual meeting of the American Association for Clinical

Chemistry in New Orleans, Wednesday, July 28, Silverman will discuss these

implications when he speaks on national efforts to standardize genetic

testing.

" Advanced molecular techniques provide a double-edged sword because

they often detect sequence changes [mutations in genes] whose deleterious

effects are by no means established, " they write.

" When we start sequencing human genes, we may find some things that are

not what we expected with that gene, " Silverman says. " We have to appreciate

that genes can operate at different levels. In CF, according to this new

concept, certain mutations that are very severe can result in the typical

disease phenotype. If other mutations are milder, more tissue-specific, you

can have ICP or CBAVD. And there are still other mutations that will just

create lesser sinus-related and pulmonary manifestations. "

The situation also may extend beyond possible tissue-specific

mutations. Mutations may be " developmentally specific. " The consequences of

the protein produced by a mutated gene would depend specifically on when

that protein is active during the individual's development, Silverman says.

" But then it also might be mutation specific, " he adds. With certain

mutations we know how the protein is altered. But what if mutations create

new functions for the protein, functions that may be deleterious? "

Thus, some mutations would not simply make the gene's protein function

less effectively. The mutation would change the protein's function. " And

that means the protein being produced has a new negative function, "

Silverman explains.

" We're arguing that mutations found with the powerful techniques for

genotyping, will not always predict the classic disease phenotype, but a

variant of it - as in the case of CF, with only a portion of the phenotype, "

he says.

Thus, several questions arise from this genotype-phenotype argument. In

people with disorders having clinical similarities to a larger genetic

disease, such as CF, do these disorders actually represent milder versions

of that disease? Should such patients be examined clinically for subtle

abnormalities of the disease that might otherwise escape detection? And

should they be genetically screened for possible disease-related mutations?

" We see patients who come in for chronic pancreatitis whom we now test

for CF mutations, " the researcher says.

For Silverman and Friedman, the genotype-phenotype argument raises

another question: " As the human genome project nears completion in 2003,

what other genetic disorders will follow a similar paradigm? "

* * *

ALSO IN TODAY'S NEWSLETTER

A Look at Genetic Testing

Genetic tests -- in particular those that can predict a person's

medical future -- are technically more difficult to perform and trickier to

interpret than conventional medical tests. And they can have a far more

profound impact on people's lives, exacting intense psychological tolls,

disrupting family relationships and unfairly jeopardizing employment and

insurability. . .

* * *

Scientists Develop New Genetic Replacement Technique In Sheep

The scientists who produced Dolly the cloned sheep announced Wednesday

that they have developed a new way to genetically design animals to produce

human medicines or organs for transplants.

Researchers at PPL Therapeutics in Edinburgh, Scotland, said they

produced four cloned sheep using a method that inactivates individual genes

and replaces them with other genes. . .

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