Human genetics: neurofibromatosis gene cloned

Article Abstract:

Type-1 neurofibromatosis (NF-1), also called Von Recklinghausen's neurofibromatosis, is an exceptionally common genetic disorder, affecting roughly 1 in 3,500 people. The majority of the patients develop non-malignant fibromas, which are fibrous tumors consisting of connective tissue, over much of their bodies; patients may have more than 500 fibromas on their skin. The gene is dominant, so that everyone who has the gene also develops the disease. However, only half of all cases result from patients passing the gene on to their children. The mutation rate for this gene is enormous; at roughly 1 in 10,000, new mutations account for almost half the cases of the disease. Such a high mutation rate generally is observed only in large genes. Simply by the laws of probability, the bigger a gene is, the more likely some random genetic event is to occur within it. Researchers were somewhat baffled when some candidate genes on chromosome 17 turned out to be quite small. When these candidate genes were sequenced, they turned out to be normal in some patients with NF-1. The identification of three patients with deletions of genetic material in the neighborhood where NF-1 was believed to reside has led to the identification of a very large gene believed to be responsible for NF-1. Researchers were surprised to find that some of the genes previously suspected as NF-1 genes were actually inside the gigantic NF-1 gene. Many genes have introns, which are pieces of DNA which will not be translated into proteins. These introns may be clipped out during the processing of RNA. In the neurofibromatosis genes, other genes are actually located within these introns. Since the disease is actually mild in some patients, the real value in a genetic understanding of NF-1 is less likely to be seen in genetic screening and counselling than in determining the source of the variability between patients. Some patients suffer severe disease, while others do not, and severity is not even consistent within single families in most cases. Therefore, the interaction of the NF-1 gene with other background genes and with the environment may be the determining factor in the severity of type-1 neurofibromatosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Medical genetics, editorial, Neurofibroma

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Paternal origin of new mutations in Von Recklinghausen neurofibromatosis

Article Abstract:

Von Recklinghausen neurofibromatosis (NF-1) is a relatively common inherited tumor. The disease is passed in an autosomal dominant fashion. The investigation of 14 families with NF-1 revealed that in 12 of these families the initial genetic mutation that caused the disease occurred in the father. A bias towards paternal origin has been observed in other genetic diseases, such as hemophilia A and Lesch-Nyhan syndrome, which also show what is called the paternal effect. If new mutations are most likely to occur during mitosis, mutations will accumulate in a male with increasing age, since the spermatogonia, which give rise to the sperm cells, continue to divide throughout life. This will not be the case in a female, in whom the oogonia do not divide. This paternal effect is not observed in NF-1. Similar findings have been reported for the inherited tumor retinoblastoma. The mutation rate of NF-1 is relatively high, but the predominance of paternal mutation cannot be explained. The mutation probably arises either in a mature sperm, or in a cell other than a stem cell. Whatever the stage at which this mutation takes place, it is more likely in males than females. (Consumer Summary produced by Reliance Medical Information, Inc.)

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A de novo Alu insertion results in neurofibromatosis type 1

Article Abstract:

Neurofibromatosis is a genetic disorder which is characterized by the development of neurofibromas (fibrous tumors composed of nerve tissue in the peripheral nerves throughout the body), bone deformities, and learning disabilities. The gene that is involved in the disorder has been identified and is known as NF1. Only a few individuals with neurofibromatosis have been genetically analyzed and mutations (genetic changes) have been found in the NF1 gene. Many different types of genetic changes in the NF1 gene are expected in various individuals. A unique type of genetic mutation has been characterized. The Alu sequence is a very repetitious segment of DNA and is present in large quantities throughout the human chromosomes. An Alu sequence was shown to be inserted into the NF1 gene. The insertion of the sequence interferes with the normal processes of the gene and protein and causes a defect which leads to neurofibromatosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

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