Heriditary panc

[Guest guest]

Interesting article about HP

C. Whitcomb, MD, PhD Editoral

It takes a family

In 1972, two physicians at the University of Indiana, McElroy and the

late Philip Christiansen, published a paper in the American Journal of Medical

Genetics on a large pedigree known as the 'S. family,' residing in the

neighbouring state of Kentucky, that was affected with a rare autosomal dominant

form of a disease called pancreatitis1. Affected individuals usually begin

to show symptoms during childhood, suffering severe and untreatable

(although not usually life-threatening) bouts of epigastric pain. The sporadic

form, which is diagnosed

more than 40,000 times each year in the United States, is usually attributable

to diets rich in fatty foods or to

alcohol, as well as to stress. Hereditary pancreatitis had first been reported

in the literature 20 years earlier, in

1952, but although the 'S. family' was one of the largest pedigrees with the

disorder on record, the report by

McElroy and Christiansen was otherwise fairly unremarkable. The low prevalence

and inability to treat the disease

did little to generate interest among fellow researchers, and an attempt to map

the gene in the late 1970s failed.

But for the Slone family, the disease was anything but rare. Indeed, in large

areas of Kentucky, their mysterious

ailment was known simply as 'Slone's disease,' reflecting the spread of the

branches of the family tree. In 1989,

, then a teenager, became so sick that he was admitted to hospital

suffering from blood clots in his pancreas

and kidney failure. He was officially diagnosed with hereditary pancreatitis,

one of just a few hundred such

diagnoses in the United States each year. The attacks were so severe that he had

to be fed intravenously, and was

not even allowed to suck ice chips. As Slone recently told the Wall Street

Journal, " You don't realize how many

food commercials are on TV until you can't eat. " 2 's father, Bobby, began

to compile a family tree, hoping to

chart the passage of the errant gene through his family. Likening himself to " a

basketball player who throws the

ball inbounds, " Slone contacted relatives and friends, slowly piecing together

information about his extended family

and marking those who had suffered from the distinctive illness. The result was

a pedigree of some 700 individuals

spanning nine generations2.

While Slone was researching his personal genealogy, researchers at the

University of Pittsburgh, led by

Whitcomb and Garth Ehrlich, decided to attempt to map and clone the gene for

hereditary pancreatitis by

collecting suitable family material. Whitcomb was hoping that the hereditary

disorder would provide a good model

for the more common (alcoholic) form of pancreatitis, and realised the project

was feasible after Ehrlich localized

the gene for Crouzon syndrome in 1994. Whitcomb contacted one of his former

colleagues, a gastroenterologist

named Lawrence Gates who had just set up a pancreatitis clinic at the University

of Kentucky, and asked him to

keep an eye out for suitable patients. Not long afterwards, Bobby Slone entered

the clinic clutching a

computerized print-out of his family tree. His son had just suffered another

relapse, and had been admitted to

hospital suffering from chronic pancreatitis (more than three quarters of his

pancreas was scar tissue). The timing

was especially fortunate, as McElroy, the physician who had first worked

with members of the Slone

family, had retired and just thrown away his records, thinking that after two

decades, no-one would have any

need for them. The search for the S. family was over; the hunt for the gene was

just beginning.

Eighteen months ago, Bobby Slone convened a family reunion at a park on the

Kentucky­Virginia border, and

while 90 relatives swapped stories, doctors took blood samples. Progress was

swift: by February this year, the

Pittsburgh team had successfully mapped the gene for hereditary pancreatitis3 to

the long arm of chromosome 7.

A French group independently reached the same conclusion4. As luck would have

it, the location not only

coincided with the known position of a pair of trypsinogen genes, but was also

in the vicinity of the ß T-cell

receptor locus, the subject of a major sequencing effort by Lee Rowen and

colleagues. Although their results5

were not yet published, much of the raw data had been deposited in GenBank,

allowing the Pittsburgh team to

exclude a number of trypsinogen pseudogenes in their search. Less than three

months after the gene had been

mapped, the gene had been found (see page 141)5.

Cationic trypsinogen is the precursor of trypsin, one of the digestive enzymes

secreted by the pancreas. The

zymogen is activated in the intestine, setting in motion a feedback loop in

which trypsin catalyses its own

conversion from the inactive precursor. Normally, a delicate balance of

activation and enzymatic inhibition is

maintained, ensuring that activated trypsin does not damage its host tissue. But

when Whitcomb et al.6 examined

the trypsinogen gene from affected members of the Slone family and four other

pedigrees, they discovered an

arginine-to-histidine missense mutation that segregated perfectly in each case.

Based on X-ray crystallography

data and good evidence that Arg 117 constitutes the main cleavage site during

trypsin degradation, the authors

believe that the Arg-to-His mutation disrupts this important cleavage site. As a

result, trypsin autoactivation would

probably proceed unchecked, and autodigestion of the pancreas thus ensues. Not

all cases of hereditary

pancreatitis are explained so neatly, however. Ehrlich's group has recently

identified a different mutation in one of

their families that seems to act somewhat differently.

One of the immediate benefits of the discovery is the opportunity to offer

counselling to members of affected

families such as the Slones. Family members are being contacted and offered the

opportunity to undergo genetic

testing, which many have indicated they would like to receive. With the basis

for hereditary pancreatitis at least

partially understood, the possible association of trypsinogen variants with the

sporadic disease can be examined.

Work is also in progress to produce valid mouse models of the hereditary

disease, in the hope of developing some effective therapies where at present,

there are none.

Since the first description of a family with hereditary pancreatitis in 1952,

only about two families per year on

average have been recorded, perhaps explaining in part why study of this rare

disease was never a priority for the

genetics community. Nevertheless, the identification of the gene offers yet

another telling example of how rapidly

research can move from linkage to locus. The authors believe their success owes

a great deal to the Human Genome Project and the welcome existence of hundreds

of kilobases of genomic sequence in their candidate region. It also serves as a

testimonial to the tireless cooperation of long-suffering families such as the

Slones. After decades of cooperation with the research community, it would be

fitting if they can finally reap some benefit.

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