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Stray 'filler' DNA disrupts normal gene.

Neurofibromatosis, a common genetic disease with widely varying symptoms, can arise when a repetitive "filler" DNA sequence pops out of its usual position and plops down in the middle of a gene thought to help regulate cell division, according to a report in the Oct. 31 NATURE.

The finding suggests that such itinerant DNA sequences -- long thought to have no vital purpose -- may underlie other genetic diseases as well.

Neurofibromatosis afflicts roughly one in every 3,500 people worldwide. Mention of the disease often evokes images of the Elephant Man, a severely deformed 19th-century Londoner named Joseph Merrick. But in 1987, the National Institutes of Health concluded that Merrick instead had the extremely rare Proteus syndrome.

The manifestations of neurofibromatosis are diverse: Some patients develop protruding, disfiguring nodules all over their trunks and limbs, while others have only barely noticeable "cafe au lait" spots discoloring their skin. The disfiguring nodules result from neurofibromas, in which the Schwann cells that insulate nerve fibers grow uncontrollably, bulging beneath the skin. Neurofibromas can painfully pinch spinal nerves.

Two research teams, working independently, announced last year that they had discovered the gene that when defective leads to neurofibromatosis (SN: 7/28/90, p.61). They named the gene NF1. Less than a month later, another investigator found that the protein normally made by NF1 belongs to the GAP (guanosine-triphosphatase-activating protein) family, whose members help regulate the timing of cell division (SN: 8/18/90, p.101). In the new report, researchers from one of the two initial teams describe in detail the mutation present in one neurofibromatosis patient.

Geneticist Francis S. Collins and his co-workers at the University of Michigan in Ann arbor report that the NFI gene of a 31-year-old man with a severe form of neurofibromatosis contained an extra, relatively short DNA sequence. The extra bit of DNA was wedged between two of the seven pieces of the NF1 gene that the body's cells normally splice together early in the protein-production process. But when the researchers deciphered the message of the inserted DNA, they discovered to their surprise that this snippet was an "Alu" sequence. Tens of thousands of Alu sequences lace the human genome, but their functions remain unknown.

These sequences, named for the enzyme first found to carve them out of human DNA in the laboratory, were previously viewed as benign "filler" DNA, neither dangerous nor beneficial. Now, for the first time, geneticists have shown that an Alu sequence can wrggle out of its usual place between genes and splice itself into a working gene, causing a disease, says Collins.

When the Michigan researchers studied the Alu insertion further, they discovered that it had caused neurofibromatosis in their patient by tricking his cells into ignoring the sixth segment of the NF1 gene. This apparently led the cells to produce an abnormal protein that unleashed their growth.

To trace the source of the man's genetic defect, the scientists compared his DNA with that of his mother and father. Neither parent bore a mutation in the NF1 gene, but the researchers were intrigued to find that the mutation arose in the copy of NF1 inherited from his father. This fit with earlier reports that most cases of neurofibromatosis arise from mutations in paternal genes.

Although Collins and his colleagues failed to find the same mutation in 50 other patients with neurofibromatosis, they remain convinced that they have stumbled upon a new genetic phenomenon. "It is likely that there will be other examples of this mechanism of mutation in human genetic disease," they predict in their report.
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Title Annotation:genetic cause of neurofibromatosis
Publication:Science News
Date:Nov 9, 1991
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