By David N. Leff

Science Editor

Back in 1969, when Bruce Beckwith announced the inherited syndrome that now bears his name, he listed all its hallmarks in the title of his journal publication: "Macroglossia [big tongue], omphalocele [protruding navel], adrenal cytomegaly [oversize adrenal glands], gigantism, and hyperplastic visceromegaly [abnormally enlarged internal organs]."

Besides all of the above birth defects, Beckwith-Wiedemann syndrome (BWS) is known today as a disease in which the cancers of childhood occur one thousand times more frequently than in the population at large.

Unlike most genetic diseases, BWS itself is not rare. It occurs in one of every 13,700 births. Which means that in recent years, over 280 infants in the U.S. alone were born with the syndrome.

"Most of these patients are born in hospitals," observed molecular geneticist Stephen Elledge, "and can get surgical attention rather quickly. The surgeons repair the problems, and then they look for cancer. Other than surgery," he added," there is no therapy for BWS. That disease has developmental abnormalities that occur in embryogenesis."

Elledge, a Howard Hughes Medical Institute researcher at Baylor College of Medicine, in Houston, is senior author of a paper in the current issue of Nature, dated May 8, 1997. Its title: "Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome." (KIP stands for kinase-inhibitory protein.)

Protein's Link To Cancer Probed

"Our goal," Elledge told BioWorld Today, "was to try to understand the role of this p57KIP2 protein in embryonic development, and whether or not its loss could result in cancer. So we made a knockout mouse," he continued, "and analyzed it to see if it had some of the same phenotypes as does the human disease. In fact, it did."

Those mice, which lack the p57KIP2 gene, the Nature paper reports, "have altered cell proliferation and differentiation, leading to abdominal muscle defects; cleft palate; bone ossification; renal medullary dysplasia; adrenal cortical hyperplasia; lens cell hyperproliferation and apoptosis."

"By analyzing the mouse," Elledge said, "we can understand what goes wrong biochemically to cause birth defects in people with BWS."

At a nittier grittier level, he and his co-authors revealed a crucial genetic feature of the p57KIP2 gene — genomic imprinting — that appears to account for some of BWS's extreme physical anomalies.

"An imprinted gene," he explained, "expresses only one of the two parental alleles, (chromosomal copies) normally passed on, one from its mother, one from its father. So effectively, a BWS baby inherits only one expressed copy of that gene."

Elledge continued: "That's why imprinted genes can give you human diseases with a much higher frequency than if you had to get rid of both alleles."

He and his group had previously cloned and mapped the p57 KIP2gene to its locus on the short arm of human chromosome 11, and showed that it was subject to genomic imprinting. "In the case of BWS," he pointed out, "it seems that only the inherited maternal copy was the expressed copy."

Only about one in 12 or 13 BWS patients get cancer, usually Wilm's tumor, adrenocortical carcinoma and hepatoblastoma. "Not all of them have mutations in this gene," Elledge said, "and it's not clear yet whether the ones that do have mutations are the same ones that get tumors, or if they're a different genetic subset.

"It's the combination of losing the expression of p57," he suggested, "which might give you all the growth abnormalities, together with losing a few other genes, that makes you more prone to cancer.

Itself a growth-suppressor, the p57KIP2 gene is indirectly related to the multi-purpose p53 tumor suppressor protein. "Actually," Elledge explained, "it's related to a gene that p53 regulates, called p21, which is also a cyclin-dependent kinase inhibitor.

"Because of BWS's peculiar genetics in imprinting," he observed, "it is a very interesting disease, which has attracted the attention of many medical people. It's one of their favorite puzzles."

Elledge's own favorite puzzle at this point is to ferret out "what are the regulators of p57 KIP2 and whether they are affected in the forms of the disease that don't have mutations in that gene.

"At least six other imprinted genes reside within one megabase on chromosome 11," he pointed out. "That's a very small amount of DNA. One-third of all known imprinted genes on the human genome are right here in this area."

One of his group's next steps "is to try to figure out if the growth factors that have opposite imprinting — expressed from the paternal gene in this region on chromosome 11 — could be the other player."

They suspect that insulin-like growth factor 2 may be such a p57KIP2-regulator, that "antagonizes it, shuts it off or destroys its protein. We're going to test the whole idea," Elledge concluded, "and see if that's the way the whole thing works. If it is, we will have explained the BWS disease almost completely." *