Genetic scientists at UAB have developed animal models of a specific type of gene mutation – called a premature stop mutation – that is responsible for 20% of NF1 cases. This innovative research initiative represents the first time that a premature stop mutation has been developed in a mouse model, providing investigators the opportunity to test new drug therapies that hold promise in restoring function to genes with this specific type of mutation.

What is a Premature Stop Mutation?

Neurofibromatosis type 1 (NF1) is caused by an alteration – or mutation – in the NF1 gene, which is found on chromosome 17. This specific gene contains a code for making a protein called neurofibromin, which is produced in many cells including nerve cells and specialized cells surrounding nerves (Schwann cells). To make neurofibromin protein, a cell must first copy information found in DNA into RNA before using the RNA to make the mature protein.  A mutation of the NF1 gene leads to the production of a nonfunctional neurofibromin protein that is unable to regulate cell growth and division, resulting in the growth of neurofibromas.

There are many different types of mutations of the NF1 gene that lead to the production of the nonfunctional neurofibromin protein, causing the development of neurofibromatosis in an individual. A specific type of gene mutation – called a premature stop mutation – is known to be responsible for approximately 20% of NF1 clinical cases. A premature stop mutation (also known as a nonsense mutation) creates a premature stop signal in the translation of the genetic code contained in messenger RNA (mRNA) in the cell. Messenger RNA carries the genetic information copied from DNA in the form of a series of three-base code “words.”  This code contains specific instructions regarding the assembly of amino acids for the production of every protein in the body. The premature stop signal that occurs during the translation process prevents the production of full-length, functional neurofibromin proteins; instead, short, nonfunctional proteins are produced that can’t regulate cell growth and division in nerve cells in the way that a normal protein does.

Developing Animal Models to Test New Drug Therapies

Animal models are useful in allowing scientists to study the process of specific diseases as well as the effectiveness of new drug treatments. These models often serve as an important foundation of drug research before clinical trials can begin in humans. UAB genetic scientists analyzed stop mutations in several families with neurofibromatosis to identify the specific point at which the premature stop signal occurs during the translation of the genetic code in mRNA. Using genetic engineering, scientists were able to reproduce the premature stop mutations in the corresponding region of the mouse NF1 gene to create two separate mouse models. Similar strategies are being used to establish zebrafish with premature stop mutations since zebrafish offer advantages in creating large numbers of offspring for experimental testing. Recreating the NF1 premature stop mutation in mice and zebrafish will enable scientists to study the NF1 disease process as it develops in the animals and to test new drug therapies that hold promise in restoring function to mutated genes.

New drug therapies currently in development have already shown effectiveness as potential treatments for other genetic disorders involving premature stop, or nonsense, mutations. These drugs work by interacting with the ribosome, the part of the cell that decodes the mRNA molecule and manufactures proteins. The drug compound allows the ribosome to read through and ignore the premature stop signals on mRNA, allowing the cell to produce a full-length, functional protein. For people with NF1 caused by nonsense mutations, this potential drug treatment would allow for the development of a functional neurofibromin protein that properly regulates cell growth and division in nerve cells.

Learn more about the UAB Neurofibromatosis Program’s leading-edge research initiatives in the following areas:

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NF1 mouse
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Stem cell lines
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NF mutation repository
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Clinical trials consortium

For more information, please contact the UAB Neurofibromatosis Program at 205-934-4983.