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Gene's newly explained effect on height may change tumor disorder treatment
August 12, 2008A mutation that causes a childhood tumor syndrome also impairs growth hormone secretion, researchers at Washington University School of Medicine in St. Louis have found.
The discovery provides new insights into an old mystery, revealing why patients with neurofibromatosis type 1 are frequently shorter than their peers. The surprising details have led scientists to consider modifying their search for treatments for the inherited disorder, which is caused by a mutation in the neurofibromin 1 (NF1) gene and is characterized by an increased risk of cancer.
"We've learned that the NF1 gene affects stature through a different pathway than the one we've previously focused on to understand cancers in patients with neurofibromatosis type 1," says Washington University neurologist David H. Gutmann, M.D., Ph.D., a Washington University neurologist who treats individuals with neurofibromatosis at St. Louis Children's Hospital. "Given that this second pathway has been linked to cancer in other contexts, we may need to consider the possibility that it is contributing to these tumors and alter our treatment goals accordingly."
The results appear online in the journal Human Molecular Genetics.
Neurofibromatosis 1 affects more than 100,000 people in the United States and is one of the most common tumor predisposition syndromes. The severity of the condition varies.
The NF1 protein, called neurofibromin, influences a number of different growth control pathways. Until now, much research focused on neurofibromin's effects on RAS protein activity, which is linked to cell growth, proliferation and cancer. Normally, NF1 deactivates RAS proteins. In its absence, scientists believe unchecked RAS can promote cancer development.
To learn more, Gutmann's lab created a line of mice in which stem cells in the brain do not make the NF1 protein. They found that these mice were significantly smaller than normal and failed to grow and gain weight after birth.
Balazs Hegedus, Ph.D., a postdoctoral researcher in Gutmann's laboratory, noticed that the pituitary glands, which produce growth hormone, also were unusually small in these mice. The amount of a second hormone that triggers growth hormone release was also greatly reduced.
"We wanted to know if we could blame this on RAS protein activity, so we generated new mice with normal levels of neurofibromin expression, but increased levels of RAS activation in brain stem cells," says Gutmann, the Donald O. Schnuck Family Professor of Neurology, and director of Washington University Neurofibromatosis Center. "However, those mice were normal."
NF1 also increases brain levels of cyclic AMP (cAMP), an important signaling molecule. Working with the same line of mice where stem cells in the brain do not make the NF1 protein, researchers fed pregnant mice and their newborns an agent that increased cAMP levels. The baby mice were closer to normal size, even though they still lacked neurofibromin in brain stem cells. Gutmann suspects the mice didn't completely return to normal because dietary supplementation of cAMP levels cannot match the natural ability of neurofibromin to control cAMP levels.
Gutmann is intrigued by the connection to cAMP. Research in other disorders has begun to build a number of associations between cAMP and tumor formation. Gutmann's laboratory and others have treatments in the works for neurofibromatosis 1 that restore the inhibitory effect neurofibromin normally has on RAS, but the new results may mean treatments are also needed to restore neurofibromin's effects on cAMP levels.
"What we've learned also may help us gain insight into other disease processes," Gutmann notes. "There are a number of other rare genetic abnormalities that cause short stature, and this same pathway may be involved."
To follow up, Gutmann plans additional studies to explore the role of the NF1 gene in the pituitary gland and the hypothalamus, a brain region that controls pituitary gland production of growth hormone.
Washington University School of Medicine
The results appear online in the journal Human Molecular Genetics.
Neurofibromatosis 1 affects more than 100,000 people in the United States and is one of the most common tumor predisposition syndromes. The severity of the condition varies.
The NF1 protein, called neurofibromin, influences a number of different growth control pathways. Until now, much research focused on neurofibromin's effects on RAS protein activity, which is linked to cell growth, proliferation and cancer. Normally, NF1 deactivates RAS proteins. In its absence, scientists believe unchecked RAS can promote cancer development.
To learn more, Gutmann's lab created a line of mice in which stem cells in the brain do not make the NF1 protein. They found that these mice were significantly smaller than normal and failed to grow and gain weight after birth.
Balazs Hegedus, Ph.D., a postdoctoral researcher in Gutmann's laboratory, noticed that the pituitary glands, which produce growth hormone, also were unusually small in these mice. The amount of a second hormone that triggers growth hormone release was also greatly reduced.
"We wanted to know if we could blame this on RAS protein activity, so we generated new mice with normal levels of neurofibromin expression, but increased levels of RAS activation in brain stem cells," says Gutmann, the Donald O. Schnuck Family Professor of Neurology, and director of Washington University Neurofibromatosis Center. "However, those mice were normal."
NF1 also increases brain levels of cyclic AMP (cAMP), an important signaling molecule. Working with the same line of mice where stem cells in the brain do not make the NF1 protein, researchers fed pregnant mice and their newborns an agent that increased cAMP levels. The baby mice were closer to normal size, even though they still lacked neurofibromin in brain stem cells. Gutmann suspects the mice didn't completely return to normal because dietary supplementation of cAMP levels cannot match the natural ability of neurofibromin to control cAMP levels.
Gutmann is intrigued by the connection to cAMP. Research in other disorders has begun to build a number of associations between cAMP and tumor formation. Gutmann's laboratory and others have treatments in the works for neurofibromatosis 1 that restore the inhibitory effect neurofibromin normally has on RAS, but the new results may mean treatments are also needed to restore neurofibromin's effects on cAMP levels.
"What we've learned also may help us gain insight into other disease processes," Gutmann notes. "There are a number of other rare genetic abnormalities that cause short stature, and this same pathway may be involved."
To follow up, Gutmann plans additional studies to explore the role of the NF1 gene in the pituitary gland and the hypothalamus, a brain region that controls pituitary gland production of growth hormone.
Washington University School of Medicine
Neurofibromatosis Current Events and Neurofibromatosis News RSSLoss of tumor supressor gene essential to transforming benign nerve tumors into cancers
Researchers at UCLA's Jonsson Comprehensive Cancer Center showed for the first time that the loss or decreased expression of the tumor suppressor gene PTEN plays a central role in the malignant transformation of benign nerve tumors called neurofibromas into a malignant and extremely deadly form of sarcoma.
New research strategy for understanding drug resistance in leukemia
UCSF researchers have developed a new approach to identify specific genes that influence how cancer cells respond to drugs and how they become resistant. This strategy, which involves producing diverse genetic mutations that result in leukemia and associating specific mutations with treatment outcomes, will enable researchers to better understand how drug resistance occurs in leukemia and other cancers, and has important long-term implications for the development of more effective therapies.
Anti-angiogenesis treatment improves hearing in some NF2 patients
Treatment with the angiogenesis inhibitor bevacizumab improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2).
Chromosomal problems affect nearly all human embryos
For the first time, scientists have shown that chromosomal abnormalities are present in more than 90% of IVF embryos, even those produced by young, fertile couples.
Rice University study finds possible clues to epilepsy, autism
Rice University researchers have found a potential clue to the roots of epilepsy, autism, schizophrenia and other neurological disorders.
Mapping a clan of mobile selfish genes
Much of human DNA is the genetic equivalent of e-mail spam: short repeated sequences that have no obvious function other than making more of themselves.
Pediatric study finds alternatives for radiation of low-grade brain tumors
A multi-institutional study led by researchers at The University of Texas M. D. Anderson Cancer Center has found that using chemotherapy alone and delaying or avoiding cranial radiation altogether can be effective in treating pediatric patients with unresectable or progressive low-grade glioma.
Anti-cancer drug prevents, reverses cardiovascular damage in mouse model of premature aging disorder
An experimental anti-cancer drug can prevent -- and even reverse -- potentially fatal cardiovascular damage in a mouse model of progeria, a rare genetic disorder that causes the most dramatic form of human premature aging, National Institutes of Health (NIH) researchers reported today.
Protein key to neuro-regeneration
Researchers at the Peninsula Medical School in the South West of England, University College London, the San Raffaele Scientific Institute in Milan and Cancer Research UK, have for the first time identified a protein that is key to the regeneration of damage in the peripheral nervous system and which could with further research lead to understanding diseases of our peripheral nervous systems and provide clues to methods of repairing damage in the central nervous system.
Research to lead to brain tumor therapies
Unique human in vitro model (cell culture) research currently underway at the Peninsula Medical School in the South West of England is set to identify and develop therapies for the treatment of multiple tumours in the brain.
More Neurofibromatosis Current Events and Neurofibromatosis News Articles
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Neurofibromatosis: A Handbook for Patients, Families and Health Care Professionals by Bruce Korf (Editor), Allen Rubenstein (Editor) Here is the state-of-the-art on recognizing, managing and living with neurofibromatosis (NF) for patients, families, and health care professionals. From new genetic and diagnostic advances, to associated cardiovascular and endocrine abnormalities, to the significant psychosocial impact of NF, the book is packed with clear, practical guidance for understanding and living with this disability. Special features - - A complete diagnostic guide to help you recognize NF-related symptoms--with a timeline for when they might appear - New treatment options for NF, including pain control - Coverage of the newly discovered form of NF, schwannomatosis - Personal perspectives from NF patients and their families - Glossary that defines medical terminology ... |
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Neurofibromatosis Medical Guide by Qontro Medical Guides (Author) The Neurofibromatosis Medical Guide is a publication which has been designed to better help readers understand Neurofibromatosis. This Qontro Medical Guide has been designed with the reader in mind, and is a useful information source for readers at all levels looking to learn more about Neurofibromatosis. The Neurofibromatosis Medical Guide is highly recommended for those interested in understanding and learning more about Neurofibromatosis. |
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Neurofibromatosis: Phenotype, Natural History, and Pathogenesis (Johns Hopkins Series in Contemporary Medicine and Public Health) by Dr. J. M. Friedman MD PhD (Editor), Dr. David H. Gutmann MD-PhD (Editor), Dr. Mia MacCollin MD (Editor), Dr. Vincent M. Riccardi MD (Editor) Univ. of British Columbia, Canada. Combines the Neurofibromatosis Institute Database with the International NF Database and the National NF Foundation. This edition sees an increased emphasis on NF2, in clinical and molecular terms. Previous edition: c1992. Includes evaluation and management, cognitive function and academic performance, and more. |
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Neurofibromatosis: a young woman's journey--case study.(Case study): An article from: Journal of Neuroscience Nursing by Susan Milliken (Author) This digital document is an article from Journal of Neuroscience Nursing, published by Thomson Gale on December 1, 2007. The length of the article is 1833 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Neurofibromatosis: a young woman's journey--case study.(Case study) Author: Susan Milliken Publication: Journal of Neuroscience Nursing (Magazine/Journal) Date: December 1, 2007 Publisher: Thomson Gale Volume: 39 Issue: 6 Page: 332(4) Article Type: Case study Distributed by Thomson... | |
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Neurofibromatosis Awareness Ribbon Mouse Pad by MyHeritageWear.com The Neurofibromatosis Ribbon proudly displayed on a mouse pad. There is no better way to achieve awareness for the meaning of the Neurofibromatosis Ribbon than to display it on your mouse pad for everyone to see. The mouse pad measures at 9.25 x 7.75, it is machine washable, and the colors will not fade or run. Start gaining awareness today by presenting your Neurofibromatosis Ribbon mouse pad at work or at home. It is certain to keep your mouse rolling in style all while gaining support and awareness! |
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Living with Genetic Disorder: The Impact of Neurofibromatosis 1 by Joan Ablon (Author) A chronicle of the life experiences of adults with neurofibromatosis 1, a neurological genetic condition for many years misdiagnosed as "The Elephant Man's Disease." Affected persons deal with an unpredictable and potentially stigmatizing disorder, the symptoms of which range from physical disfigurement to severe learning disorders. Ablon offers suggestions for families, support systems, and health care providers to enhance coping skills and self image of the affected persons. |
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ABC News Nightline Listen Lesson in Patients ABC News looks at how Harvard Medical School is creatively teaching its students one of the most important skills for a physician - how to listen to their patients. ABC News also meets Porter Colley, a 73- year old woman who suffers from neurofibromatosis. Airdate: 9/1/2000 This product is manufactured on demand using DVD-R recordable media. Amazon.com's standard return policy will apply. |
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Neurofibromatosis: Trusting God in the midst of NF by Renee B Wilson (Author) | |
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Neurofibromatosis Type I in Childhood by Kathryn North (Author) A great deal is now known about neurofibromatosis type 1, particularly as a result of the identification of its causative gene by positional cloning. However, effective treatments for its resulting cosmetic disfigurement, impaired cognitive performance and even life-threatening malignancy remain elusive. As Dr. Korf remarks in his Foreword: "this book's cogent and thorough description of neurofibromatosis in children will take its place alongside other major clinical studies of the disorder. [Dr. North] has tackled some of the more challenging issues, such as the basis for learning disabilities and the optimal means for early detection of optic gliomas. Her work provides a guide to the clinician and stands as a provocative challenge to the neurofibromatosis research community to further... |
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Neurofibromatosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References by ICON Health Publications (Author) In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading." Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing.This book was created for medical professionals, students, and members of the general public who want to conduct medical research using the most advanced tools available and spending the least amount of time doing so. |
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