Clue to Elephant Man Illness Found : Genetics: Discovery of the gene that causes the disfiguring ailment could speed development of ways to treat it.
Utah and Michigan investigators have independently discovered the defective gene that causes Von Recklinghausen neurofibromatosis, commonly known as Elephant Man’s disease.
Neurofibromatosis is the most common nervous system disease caused by a single gene defect, affecting one out of every 3,500 people worldwide, including an estimated 100,000 Americans. Its symptoms range from skin discolorations to mental abnormalities to debilitating tumors of the nervous system.
The discovery of the gene, reported today in the prestigious journals Science and Cell, should quickly make possible prenatal and newborn screening for the disorder. The next step will be identifying the protein produced by the gene, which should enable development of new forms of therapy for the disease.
“This is a feat that will rank as one of the great moments in genetic research,” said Peter R. Bellerman, president of the National Neurofibromatosis Foundation. “It will change the lives of the people we represent.”
Added molecular biologist Raymond L. White of the University of Utah School of Medicine: “We now look forward with great enthusiasm to unraveling--probably within the next several years--the fundamental mechanisms of this disease.”
Surprisingly, the researchers also found that the neurofibromatosis gene contains, embedded within it, three other genes.
This marks the second time in recent months that an unexpected gene has been found within a gene, and researchers speculate that it may reveal the existence of a previously unknown mechanism for controlling genes.
Neurofibromatosis, first described in 1882 and often called NF1, has a broad spectrum of symptoms and severity. The most common features include flat, pigmented skin lesions called cafe-au-lait spots, growths on the iris and benign tumors, which increase in size and number with age.
More severe complications include large, deforming growths in “Elephant Man” fashion and sometimes malignant and fatal tumors of the nervous system. As many as six of every 10 people with the disorder have learning disabilities; seizures, scoliosis and brain tumors can also occur. There is no treatment for the disorder other than surgical removal of the tumors.
A second and rarer form of the disease, called bilateral acoustic neurofibromatosis, or NF2, strikes one in every 50,000 people, causes brain tumors and commonly leads to deafness. Its cause is still unknown.
Children of a parent with NF1 have a 50% chance of developing the disorder, but as many as half of all cases are not inherited. Instead, they arise from a spontaneous mutation in the newly discovered gene.
Interest in the disorder was heightened in recent years by the hit play and movie about John Merrick, the disfigured 19th-Century Englishman who was once thought to have it. Recently, however, researchers have concluded that Merrick had a similar but rarer disorder called Proteus syndrome, which involves a different genetic defect and causes more disfiguring.
Like Merrick, victims of NF1 are stigmatized. Typical of them is Porter Colley, a Massachusetts woman who has suffered with NF1 since it was diagnosed when she was 12. Colley appeared at the Washington press conference at which the discovery was announced, her face and hands covered by hundreds of dime-sized tumors.
Her voice cracking with emotion, Colley said: “I have been the subject of frequent ridicule and social isolation. . . . It’s as if people with NF were singled out for a particularly cruel life. . . . As a person living with NF, this is one of the best pieces of news I have ever had. It’s affecting me deeply.”
The University of Utah’s White headed one of the two teams that discovered the gene. The second team was headed by geneticist Francis S. Collins of the University of Michigan Medical Center, who was also a key member of the team that last year reported the discovery of the defective gene that causes cystic fibrosis.
Researchers had known for several years that the NF1 gene was located in a specific region of chromosome 17, but had had difficulty pinpointing it. The identification came after the researchers discovered two new NF1 patients who had a break in chromosome 17 at the same site, within the region that had previously been identified.
Finding the break enabled the researchers to narrow the region of DNA--deoxyribonucleic acid, the genetic blueprint of life--to be searched, thereby speeding up isolation of the gene.
The researchers have not yet discovered the gene’s function, but they believe it belongs to a recently discovered family of genes called tumor suppressors. Such genes, first identified in 1986, serve to keep the growth of cells in check. When they are defective, however, cell growth is unrestrained, leading to the formation of tumors.
“If this is a tumor-suppressor gene,” Collins said, “it is likely that it plays a role not only in this rare genetic disease, but (also) in more common disorders” such as cancers.
The researchers are also eager to learn the role of the three genes they found embedded within the NF1 gene. The genes, interestingly, are oriented backward, like a sentence reading from right to left.
The only previous instance of such embedded genes in humans was reported earlier this year by molecular biologist Jane M. Gitschier of UC San Francisco, who found one within the gene for the protein that causes the bleeding disease called hemophilia. Its function is also still unknown.
Collins speculated that the embedded genes might help regulate the activity of the NF1 gene. Alternatively, he said, one of the embedded genes may be important in the functioning of the brain, which would explain the link between NF1 and learning disabilities.
Maugh reported from Los Angeles, Cimons from Washington.
