Neurofibromatosis 1 (NF1) is caused by a mutation in the NF1 gene on chromosome 17. NF1 is a large gene; the 60 coding regions of the gene — exons — are spread out over 350 kilobases.  This gene makes a protein called neurofibromin. By making slightly different mRNA, the body can control where and when neurofibromin is found.  One of three exons is included in the mRNA; this differential splicing produces at least three slightly different neurofibromin proteins that are then directed to different tissues. Neurofibromin is expressed at a very specific time in development in the forebrain and also found in neurons, muscle and other tissues. Although neurofibromin is found in different tissues, all neurofibromin have a very important region called the “GAP-related domain.” This is the only region of the protein whose biological function is known.  This region of neurofibromin is believed to act similarly to Ras — a key protein involved in the control of cell growth and proliferation. In cells, a cascade of “activated” proteins act as a signaling pathway for a number of cellular processes.  Proteins like Ras can be activated by the addition of a phosphate group; removal of the phosphate group deactivates Ras. GAP stands for GTP-ase activating protein.  Neurofibromin, as a GAP protein, acts to speed up the deactivation of Ras by the removal of the phosphate group.  This in effect “turns off" parts of the cell growth and proliferation pathways. When neurofibromin is absent or not working properly, as in the case for people with neurofibromatosis, Ras is in an active state and cells can grow and proliferate, leading to tumors.  Malignant tumors associated with neurofibromatosis are most likely due to a second mutation that inactivates another protein, p53, in the signaling pathway. Other types of tumors and symptoms associated with neurofibromatosis may be due to the amount of mRNA processing leading to the expression of neurofibromin in different cell types. Neurofibromatosis 2 (NF2) is caused by a mutation in the NF2 gene on chromosome 22.  This gene produces a protein called merlin or schwannomin. Merlin is expressed in nerve cells, specifically schwann cells, which wrap around the axons of nerve cells.  NF2 is usually an adult-onset disorder; people with NF2 develop tumors of the schwann cells around the nerves of the ear. Merlin can bind to a receptor protein called CD44, which is found in the cell membrane.  This binding suppresses cell growth. If merlin is mutated or absent, as is the case for people with NF2, cell growth and proliferation is uncontrolled.  Thus, merlin is a tumor suppressor protein. Merlin is also related to the ERM family of proteins, which seem to link proteins in the cell membrane to the cytoskeleton.  The cytoskeleton is the internal framework of the cell.  Cytoskeletal components, like actin, are  important for cell growth and movement. There is evidence with cells grown in culture that when merlin is mutated, the organization and control of cytoskeletal components is lost, leading to cell proliferation and spread.  In the body, the loss of cytoskeletal organization due to a merlin mutation may lead to cell movements resulting in tumor growth in other parts of the body – metastisis. DNA diagnostic tests are available for both NF1 and NF2.  However, NF1 is still mostly diagnosed based on clinical symptoms.  Because NF2 is a late adult-onset disorder, a DNA diagnostic test can be done for children who have a family history of NF2. The NF2 DNA diagnostic test compares DNA between someone who is suspected of having NF2 and someone who does not have NF2.  To do this, many copies of the NF2 gene are made using a technique called polymerase chain reaction (PCR).  Short stretches of DNA called primers are added to DNA from someone who does not have NF2. Primer A attaches to the DNA just to the left of the NF2 gene, while primer B attaches just to the right of the NF2 gene. Short stretches of DNA called primers are added to DNA from someone who does not have NF2. Primer A attaches to the DNA just to the left of NF2 gene, while primer B attaches just to the right of the NF2 gene. After the primers attach, a chemical reaction called PCR (polymerase chain reaction) essentially makes millions of identical copies of the DNA that lies between the two primers.  Each copy contains the NF2 genetic information. The same set of primers are used in a PCR reaction using DNA from someone who is suspected of having NF2.  Again, many copies of the NF2 gene are made. As single-stranded DNA, these PCR pieces have specific shapes.  The shapes are dependent on the DNA sequence.  Any changes to the sequence can change the shape of the single-stranded DNA. A mutated NF2 gene will have a different DNA sequence and thus a different single-stranded shape than a non-mutated NF2 gene.  This shape difference can be resolved by using an electric current to run the single-stranded DNA through a special gel. The single-stranded DNAs are loaded onto different lanes of a gel. An electric current sent through the gel pushes the DNA pieces down toward the bottom of the gel. A closer look shows that as the DNA move down the gel, they have to make their way through the tangled molecules of the gel.  The single-stranded DNAs move differently through the gel; different shapes move at different speeds. If the child does have a mutation in his NF2 gene, his single-stranded NF2 DNA will not migrate to the same spot as that of someone who doesn't have an NF2 mutation.  This type of analysis, called single-strand confirmation polymorphism (SSCP), is useful when the exact mutation is not known or when there are too many different mutations to test for. What isit? What causes it? How is it inherited? How is it diagnosed? How is it treated? What is it like to have it? For more information…Acknowledgments. Clinical Signs Dr. Allan Rubenstein is an NF specialist. He talks about the clinical signs of NF1 and NF2 used for diagnosis. Early Indications Dr. Allan Rubenstein gives more details on early signs on NF1 Cancer Risks Dr. Allan Rubenstein talks about cancer risks in people with NF1. NF1 Variabiliy Noel Kaeck inherited NF1 from her father. Her mother, Cara, talks about the different symptoms between father and daughter. Dr. Allan Rubenstein comments on the variability of symptoms in people with NF1. Half the people with neurofibromatosis 1 (NF1) inherit the disorder from a parent who also has the disorder. NF1 is caused by a mutation on chromosome 17 and is more common than NF2, which is caused by a mutation on chromosome 22.  Let's look at how someone can inherit NF1. The disorder can be inherited from the mother if she passes the NF mutation to the child, or from the father if he passes the mutation to the child. NF1 is a large gene that spans over 350 kilobases.  Mutations can be deletions or single base changes in the DNA sequence, which result in the non-production of the protein neurofibromin and the development of NF1. Though they share the same mutation, the affected child and parent may not have the same NF1 symptoms.  This child may have small benign tumors, whereas her affected parent may have large tumors and learning disabilities.  It is likely that other genes and environmental factors account for the wide variability of symptoms among people with NF1. In the remaining half of people with NF1, neither parent has the disorder.  These people develop the disorder when one of their NF1 genes spontaneously mutates before birth.  In this example, the gene mutates during the production of one of the mother's eggs and is passed to the child. NF1 is a large gene so there is a good chance of spontaneous mutations occuring.  Every unborn child in the world has a 1 in 10,000, or 0.01%, chance of getting NF1 through a spontaneous mutation. Both NF1and NF2 are dominant disorders and are inherited and passed on the same way.  When one parent has a mutated NF gene, the chance of his/her child inheriting the disorder is 50%.  In this couple, the father has the NF-causing mutation (N) and the normal gene (n), while the mother has two copies of the normal gene. A Punnett square illustrates their possible children, and lets us calculate the chance each child has of inheriting the disorder.  First, we arrange each parent's genes on the outer edges of the square. Each parent donates one of their NF genes to the child, so we place one of the father's genes and one of the mother's genes into each box.  Each completed box shows a potential combination (or genotype) in the child, and the entire square contains all possible combinations. Next, we count the boxes that contain a NF-causing genotype (the Nn combination).  2 out of 4 boxes contain this combination, so the chance of this couple's child inheriting NF is also 2 out of 4, or 50%.The same chance applies in the opposite situation when the woman has the NF mutation and the man does not. The same chance applies in the opposite situation when the woman has the NF mutation and the man does not. Two out of four boxes contain the NF-causing combination (Nn or nN), so the chance of this couple's child inheriting NF is also 2 out of 4, or 50%.The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 50% chance of receiving the mutation. In this family, one in four children has NF.  Other couples with the mutation may have two, three, four, or even no children with NF. NF2 is more of an adult-onset disorder.  People with NF2 develop growths around the vestibular nerve of the ear, which can lead to deafness.  Growths in other parts of the central nervous system, brain, and spinal cord, can also develop.  These growths are usually benign, however, their location makes NF2 difficult to treat. Facts and Theories symptoms NF1 NF2 Incidence Testing and Screening Cause Treatment People with NF1 may have a number of pigmented spots on the skin known as "café-au-lait" spots because of their color.  Benign growths called neurofibromas can develop throughout the body; this can cause bone abnormalities. The size and number of neurofibromas and café-au-lait spots are variable among people with NF1.  People with NF1 may also have learning disabilities. Neurofibromatosis (NF) affects both sexes and all ethnic groups.  NF1 is more frequent and has an incidence rate of 1 in 4,000.  NF2 is rarer and has an incidence rate of 1 in 40,000. DNA tests are available for NF.  However, because there are so many different mutations of the NF1gene, diagnosis is usually dependent on clinical symptoms.  DNA tests can help identify children who have NF2, but haven't yet developed any symptoms. Neurofibromatosis (NF)  refers to two genetically- distinct dominant disorders.  NF1 is caused by a mutation in the NF1 gene on chromosome 17.  NF2 is caused by a mutation in the NF2 gene on chromosome 22. There is no known cure for neurofibromatosis — NF1or NF2.  People with NF can have surgery to remove neurofibromas.  This can be tricky as NF1 and NF2 tumors can be located in the brain or other parts of the central nervous system. Neurofibromatosis (NF) refers to two genetically distinct disorders: NF1 and NF2.  NF1 affects the peripheral nervous system; NF2 affects the central nervous system.  In both disorders, tumors develop from nerve tissue. Surgery Dr. Allan Rubenstein is an NF specialist. He talks about surgery as an option for people with NF1. Surgical Experience Cara and Noel Kaeck talk about the surgical experience. Noel has had many surgeries to control the growth of her facial tumor. Emotional Support Dr. Jane Halperin is a clinical psychologist and a genetic counselor who works with people with NF. She talks about the psychological impact of nf1 and the need for emotional support. Learning Specialist Dr. Jame Halperin talks about ways to identify and help an NF child with learning disabilities. Medication Noel and her mother, Cara, talk about taking the medication carbitrol to control Noel’s seizures. Prenatal Counseling Dr. Jane Halperin comments on why genetic counseling is important for people with genetic disorders, ad some of the issues involved with prenatal decisions for people with NF1. Diagnosis and Reactions Cara Kaeck talks about when her daughter Noel was first diagnosed with NF and her reactions to the news. Noel’s Words Noel is eight years old, and this is what she wants people to know about NF and what it is like to have it. NF Misconceptions Cara talks about people’s misconceptions of NF and how this could be problematic in dealing with doctors and getting the correct treatment. Staring Noel and Cara talk about people who don’t know about NF and who stare at Noel’s facial growth. Advice for Parents Cara talks about how to cope with having a child with a serious medical condition like NF. Education Cara discusses the difficulty of dealing with a school system that still insists on standardized exams and tests for Noel who does have learning disabilities. Behavior Cara talks about some of the reasons for Noel’s behavioral problems. Noel is a child with NF but she is still a child. Healthcare and Insurance Cara talks about dealing with the insurance companies and getting bills paid. 
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