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Human Genome News Archive Edition

Human Genome News, September 1990; 2(3)

Neurofibromatosis Gene Discovered

Researchers affiliated with the Howard Hughes Medical Institute (HHMI)-one group at the University of Utah School of Medicine and another at the University of Michigan Medical School- have identified the gene believed to be responsible for von Recklinghausen neurofibromatosis (NF1), the most common nervous system disease caused by a single gene defect. These investigators also uncovered a rare biological feature that emphasizes the complexity of human genetics.

The findings were reported in the July 13 issues of two journals: Cell [62: 187-192, 193-201 (1990)] by Raymond White, leader of the research team at Utah, and Science [249: 181-186 (1990)] by Francis Collins, who directs the Michigan group. White and his team earlier identified mutations that lead to colon cancer and retinoblastoma (see related articles, White and Cavanee Share Mott Prize and Recent Studies by Mott Awardees). In 1989 Collins and a group of collaborators in Canada identified the gene for cystic fibrosis, the most common fatal genetic disorder among Caucasians.

The NF1 form of neurofibromatosis affects more than 1 in 4000 newborns, with symptoms ranging from skin discoloration and learning disabilities to debilitating and sometimes fatal tumors of the peripheral nervous system. As many as 100,000 Americans have the disease. Children with one parent having a defective NF1 gene have a 50% chance of developing the disease. Nearly half of all cases of NF1 are not inherited, however, but are caused by new genetic mutations that occur early in development. NF1 often escapes detection until age 4 or 5, but if the gene discovery aids in early diagnosis, effective intervention may someday be possible.

Neurofibromatosis was mistakenly believed to be the cause of the deformities of Joseph Merrick, a nineteenth century Englishman who became known as "the Elephant Man" and was the subject of a popular movie and play. Health experts have since concluded that Merrick suffered from a different disorder-Proteus syndrome.

Since the protein product of the defective NF1 gene had not been isolated, investigators used the relatively new approach sometimes referred to as reverse genetics or positional cloning. This method of locating disease genes has succeeded with six others, including those for cystic fibrosis, muscular dystrophy, retinoblastoma, and Wilms' tumor.

In 1987 a group of medical statisticians led by Mark Skolnick (University of Utah) collaborated with White's group to use genetic linkage studies to establish the NF1 locus on chromosome 17. Linkage studies further narrowed the area to which the NF1 gene could be located, and the Michigan and Utah researchers employed novel techniques such as chromosome jumping (developed by Collins' group) and yeast artificial chromosomes.

The Utah scientists recognized that a well-studied region of mouse DNA suspected to be involved in murine leukemia was similar to DNA sequences that mapped to the 50 kb of DNA between the NF1 translocations; they characterized three small genes in this region, but none of the three showed NF1-specific point mutations. In intensive comparative studies of normal and NF1 individuals, both research groups identified and sequenced complementary DNA clones from a region showing rearrangements of genetic material in NF1 patients and predicted that the fourth gene in the translocation region would be likely to cause neurofibromatosis. The researchers showed that NF1 patients had point mutations in the gene's coding region, thus proving that mutations causes NF1.

Less than a month after publication of the NF1 gene's partial DNA sequence, White's group published findings that extended the sequence and examined the predicted NF1 peptide for similarities with known proteins [Cell 62: 599-608 (1990)]. These studies suggested a functional homology of the NF1 peptide and the catalytic domain of the mammalian GTPase-activating proteins and their yeast counterparts, IRA1 and IRA2. The genes coding for these proteins are known to be involved in the mechanisms controlling cell growth and differentiation.

Taken together, these studies suggest that the NF1 gene controls cell growth; when the gene malfunctions, cells grow out of control and cause tumors. Collins noted that NF1 patients have a slightly higher risk for brain tumors and various other cancers, so studies of the NF1 gene may also yield new insights into various malignancies.

Identification of the NF1 gene also disclosed a rare biological feature that may have far-reaching implications: the three smaller genes are embedded in the NF1 gene and are oriented in the opposite direction; this is only the second time genes located within other human genes have been reported. Jane Gitschier at the University of California, San Francisco, recently reported finding a separate gene of unknown function embedded within the gene responsible for classic hemophilia (the factor VIII gene). This embedded gene was also in reverse orientation [Genomics 7(1): 1-11 (1990)].

Commenting on this unusual finding, Collins remarked that genes may be much more complex than previously thought. The embedded genes may have some function in the regulation of gene expression and may have implications for researchers looking for disease genes. These genetic challenges underscore the timeliness of the Human Genome Project, which seeks to identify all 50,000 to 100,000 genes.

Research Update:
White's laboratory at the University of Utah has predicted a function for the NF1 protein, raising hope that neurofibromatosis may one day be treatable. See August 10 issue of Cell [62: 599-608 (1990)]

NF1 Gene Research Sponsors:

  • HHMI
  • National Neurofibromatosis Foundation
  • NIH National Institute of Neurological and Communicative Disorders and Stroke


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Human Genome Program, U.S. Department of Energy, Human Genome News (v2n3).

Human Genome Project 1990–2003

The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.

Human Genome News

Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.