Neurofibromatosis Type 1 (NFN1/NF1) is a monogenic disease arising from the germline mutation of the NF1 gene (Ritsuko Harigai, 2018). Located in the chromosome region of 17q11.2 (as shown in fig 1 below), this gene encodes for a 2818-amino acid protein called Neurofibromin (Ritsuko Harigai, 2018). This protein is important in the body because it is a tumour suppressor protein which plays a vital role in the regulation GAP and RAS proteins (Ritsuko Harigai, 2018). When this gene undergoes mutation, it becomes inactivated and it loses its ability to encode for this neurofibromin protein which has the ability to suppress the growth of a tumour (Bodapati Chandra Mouleshware Prasad, 2018). This gene also affects how some other genes are expressed such as the BRCA1 gene which is associated with breast cancer (Bodapati Chandra Mouleshware Prasad, 2018). People suffering from the inability to produce this NFN1 gene are said to have Neurofibromatosis. This disorder is commonly a neurocutaneous autosomal dominant disorder that is mostly inherited and not unique to any sex or a particular ethnic or racial group with about 1 in 2000-3000 people across the world living with this disorder (Parisa Sharafi, 2018).
It has a highly unpredictable clinical phenotype, but people living with this condition are often characterized by café’-au-lait spots (CLS), Lich nodules, axillary and inguinal freckling, multiple peripheral nerve tumours and benign tumours (Parisa Sharafi, 2018). This work is aimed at investigating the origin of the genetic defect giving rise to this condition, and in light of this, it would further explore the impact of this mutation on the biochemical and cellular processes of the body.
Around the central region of the NFN1 gene is a sequence of an amino acid consisting of about 360 amino acid. The size of this gene is about 350kb and contains about 58 exons, but it codes for a 12kb mRNA (Bodapati Chandra Mouleshware Prasad, 2018). The sequence of this 12kb mRNA is similar to the catalytic area of the GTPase-activating protein (GAP) (Parisa Sharafi, 2018). This region is often referred to as the NF1-GAP-related domain (NF1-GRD) (Parisa Sharafi, 2018). By stimulating the intrinsic activity of GTPase, these proteins are used to suppress the activities of the RAS oncoprotein making Neurofibromin part of the RAS-mediated signal transduction system (Parisa Sharafi, 2018).
Figure 1: Fig a ; b above shows the location of chromosome 17q11.2 where the NFN1 gene resides. It also shows the functional domains associated with the mRNA that goes ahead to code for the Neurofibromin protein. (Bodapati Chandra Mouleshware Prasad, 2018)
Neurofibromin facilitates the quick conversion of active guanosine triphosphate bound RAS (RAS-GTPase) to an inactive form guanine diphosphate bound RAS (RAS-GDP) leading to a reduction in the level of RAS-GTPase and subsequently the activities of RAS including unregulated cell growth (Deborah R. Gold, 2003). In the absence of this protein, RAS levels are higher than normal leading to an increased possibility of tumour formation (Deborah R. Gold, 2003).
When Incoming signals switch on the RAS-GTPase proteins, it leads to the activation of the genes responsible for cell growth and differentiation. In the absence of neurofibromin protein, the RAS-GTPase signalling would become over-activated leading to an unrestricted cell growth causing the formation of a tumour. The pictorial representation of this process is shown in figure 2 below.
Figure 2: Fig showing the inability of Mutated NFN1 to activate RAS-GTPase leading to type1 neurofibromatosis. (Bodapati Chandra Mouleshware Prasad, 2018).
Mutated Neurofibromin operates as a negative regulator of RAS proteins (Ritsuko Harigai, 2018). It down-regulates RAS proteins by using its RAS-GTPase activity to alter the activity of RAS-GTP protein, thereby inactivating the GDP-bound RAS in the process (Bodapati Chandra Mouleshware Prasad, 2018). By inactivating RAS, other pathways such as the PI3K, Akt, MEK, RAF, mTOR, ERK, S6, differentiation and cell proliferation pathways are also suppressed (Bodapati Chandra Mouleshware Prasad, 2018). The dysfunction of these pathways could also lead to multiple other disorders as they have an effect on other associated genes such as the BRCA1 genes (breast cancer 1), HRAS gene (v-Ha-ras Harvey rat sarcoma viral oncology homolog), NRAS gene (neuroblastoma RAS viral oncogene), SDC2 gene (syndecan 2), TBPL1 gene (TBP-like 1), GTF2B gene (general transcription factor IIB), etc. (Bodapati Chandra Mouleshware Prasad, 2018). These disorders often have similar phenotypical expression hence are often classified as Rasopathies (Parisa Sharafi, 2018). Figure 3 below shows some of the proteins that have an interaction with the neurofibromin protein and their respective domains relative to each other.
Figure 3: Location of some of the protein interacting with Neurofibromin protein.
The figure above is a representation of some of the proteins that interact with neurofibromin protein and their domains shown in light blue. Proteins that interact with neurofibromin protein are represented in ovals with the colour of the ovals showing the function they perform. The lower figure is a schematic overview and representation of the frequency and general location of the various types of mutations in the NFN1 gene (Parisa Sharafi, 2018).