Neurofibromatosis Type 1
Nicole Foley

Neurofibromatosis Type 1, also known as Von Recklinghausen Disease affects 1 in 3,500 people worldwide. It is caused by various mutations in the NF1 gene on chromosome 17q11.2 [Viskochil 2002]. NF1 gene codes for the production of the protein neurofibromin, which acts as a tumor suppressor by positively controlling adenylate cyclase activity and intracellular cyclic AMP levels [Gutmann et al 2012].
Neurofibromatosis is characterized in infected children by changes in skin color known as café-au-lait spots, which are darker patches of skin. During childhood and into adolescence the child will develop larger spots, freckles in the armpits and groin area, and eventually benign tumors alongtheir nerves in the skin, brain, eyes (Lisch nodules), and other location throughout the body known as cutaneous neurofibromas. Tumorigenesis is the main symptom and concern in individuals with Neurofibromatosis Type 1. Neurofibromas may affect any organ in the body. Fifty percent of people infected with NF1 also suffer from learning disabilities[ Friedmann et al 2012].
NF1 is inherited in an autosomal dominant pattern, therefore only one copy of a particular gene mutation is inherited on a non-sex chromosome [Rasmussen et al 2012]. This single mutated copy of the gene alone is enough to cause the disease and the symptoms seen in childhood, yet a second mutation is required for tumor formation to occur. This second somatic mutation occurs in the wild type NF1 allele in adulthood. It inactivates the wild type allele function, which causes the individual to have complete inactivation of neurofibromin and to therefore experience tumorigenesis [Laycock-van Spyk et al 2011]. This second somatic mutation actively speeds up the growth of tumor cells and causes the benign tumors to turn malignant. The presence of malignant tumors contributes the most to morbidity in patients with Neurofibromatosis type 1[ Alkindy et al 2012].

Image obtained from Wikipedia public domain.Licensed under the Creative Commons Attribution-Share Alike 3.0 .

Neurofibromatosis is a very difficult disease to study and treat because it is characterized by extreme clinical variability between unrelated individuals, related individuals, and a single individual over time. Close to 1000 mutations have been identified, with the more unique ones being localized to a single family. A sequence analysis revealed that ninety percent of NF1 cases were caused by a intragenic mutation [ Friedmann et al 2012]. NF1 mutation rate is among the highest observed in humans, with ninety percent of new mutations occurring on the paternally derived chromosome and large gene deletions occurring on the maternally derived chromosome [Rasmussen et al 2000]. There are four distinct classes of NF1 mutations; truncating, missense, in-frame deletions, and large deletions[ Sabbagh et al 2009]. Each mutation can present itself in a different way in each infected individual, creating an immense number of variable phenotypes, even in those individuals with the same NF1 mutation. The genotype-phenotype relationship in NF1 patients has been the sole focus of many studies on Neurofbiromatosis type 1. Two phenotypes have been identified and characterized throughly; Noonan Syndrome and Leopard Syndrome. Three clear correlations have also been discovered between a particular mutant allele and a phenotype.

1. Whole deletion of the NF1 gene, which leads to an earlier appearance and increased number of cutaneous neurofibromas, along with more frequent and severe cognitive disabilities.

2. base pair in-frame deletion of exon 17 associated with café au lait spots and freckles but no cutaneous neurofibromas.

3. Duplication of entire NF1 locus, intellectual disabilites and seizures but no NF1 clinical features (café au lait spots, Lisch nodules, freckles)[ Friedmann et al 2012].

The extreme clinical variability and genotype-phenotype correlations suggest that other factors may be involved in the clinical manifestations of the disease, these features also make the disease extremely complex and difficult to treat.


Image obtained from a Public Blog established and maintained by an individual suffering with NF type 1. Permission obtained to use chart.

Research Questions:
Which gene is involved?
Are there gender differences in regards to mutations present and the genotype-phenotype correlations?
Is the responsible gene and gene mutations present across species?

Genetics and Mechanisms of NF1 Gene Diagnosis and Treatment NF1 Genotype-Phenotype Correlations Neurofibromatosis Type 1 Methods conclusions Works Cited