Neurofibromatosis type 1 (NF1), with an incidence of 1 in 3,500 persons, is the most common inherited disease that predisposes to tumor formation. Although all individuals who carry a mutation in the NF1 gene also show symptoms of the disease, the severity of these symptoms varies widely between individuals. Some NF1 patients have only pigmental abnormalities whereas others have hundreds of neurofibromas and other tumors. The reason for this variability is not known. This proposal aims at elucidating one possibility for the observed variability, namely a difference in the genetic composition of mitochondria in the cells of patients.

Individual clinical variation seen in genetic disorders is often caused by an influence of modifier genes or environmental factors. None of those could be identified in NF1, but it is very likely that those modifiers exist. Mitochondria are small organells that are present in every cell of the body. Mitochondria are responsible for a cell¿s energy production, but they are also involved in regulating other cellular processes such as cell death and mutagenesis. Mitochondria are important players in some tumors, and diseases caused by mitochondria are often heterogenous, variable in expression, segmental and mosaic, resembling the clinical picture seen in NF1.

We propose that a subclass of mitochondria is dominant in NF1 patients with severe symptoms and absent in NF1 patients with mild symptoms. To find these mitochondrial subclasses, we will use genetic markers, called polymorphism, which can identify mitochondria. This genetic approach does not need information on possible function of mitochondria in NF1.

For our study, we will divide NF1 patients into two groups: patients with severe symptoms and patients with mild symptoms. Blood will be taken from these patients and mitochondria from blood cells will be classified. Then, the mitochondrial classes from each patient group will be compared. In addition, it might be that in an NF1 patient only cells that form tumors are different from normal cells with respect to mitochondria composition. Thus, when mutated mitochondria are amplified in a cell, this cell can develop a tumor, but a neighboring normal cell does not. To study the mitochondria composition of tumors in NF1, dermal neurofibromas will be collected and their mitochondria compared to normal cells of the same patient.

The type of mutation in mitochondria observed in NF1 that leads to a severe phenotype could shed light on another aspect of neurofibromin function. This information also can be used to predict the risk of severe symptoms in NF1 and might lead to some preventive measure.