CSRD: cysteine-serine rich domain, TUB: tubulin binding domain, GRD: GTPase-activating protein-related domain, PH: pleckstrin homology; CTD: carboxy-terminal domain; SBD: syndecan-binding domain; DDAH1: dimethylaminohydrolase 1, P: phosphorylation, protein kinase A substrates; APP: amyloid-? precursor protein; DPYSL2: dihydropyrimidinase-related protein 2; FAF2: FAS-associated factor 2; FAK: focal adhesion kinase, LIMK2: LIM domain kinase 2; LRPPRC: leucine-rich pentatricopeptide motif-containing protein; SCF: Skp, Cullin, F-box-containing complex; VCP: valosin-containing protein (Parisa Sharafi, 2018).
The phosphorylation of Neurofibromin protein by protein kinase C (PKC) along the cysteine-serine rich domain (CSRD) improves the function of the protein in the RAS-GAP regulation (Bodapati Chandra Mouleshware Prasad, 2018). A mutation occurring in the region of the NFN1 gene responsible for coding the Neurofibromin protein affects the functionality of the PKC phosphorylation of the normal Neurofibromin causing Neurofibroma (disease resulting from the occurrence of benign tumours in peripheral nerve sheath) (Bodapati Chandra Mouleshware Prasad, 2018).
It has been recently discovered that embedded within the 27b intron region of the NF1 gene are three obscure genes which are the EV12A, EV12B and OMGP genes. (Parisa Sharafi, 2018). The only thing known about these genes is that they are transcribed in the opposite direction to the NF1 gene. The NFN1 gene easily undergoes mutation with about fifty percent of the cases occurring as a result of de novo mutations (Parisa Sharafi, 2018). As a result of the deficiency in the mutation hotspot and due to the wide mutation spectrum of the NFN1 gene, it has been very difficult to identify the mutation that gives rise to NFN type 1 diseases (Parisa Sharafi, 2018).
Bodapati Chandra et al, carried out a study on three successive generation of 3 unrelated Indian families who were suffering from Neurofibromatosis Type 1 (NFN1). Their successive family tree is as shown below.
Figure 4: The family tree of three unrelated Indian families living that have NFN1. It shows three successive generations of the suffers (Bodapati Chandra Mouleshware Prasad, 2018)
The summary of the clinical characteristics of the family is as shown in the table below
Table 1: Summary of clinical characteristics of NF1 Patients. (Bodapati Chandra Mouleshware Prasad, 2018).
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The table 1 above shows the age, sex, and other physical manifestation of this conditions on the participants for this experiments.
Table 2: Identified gene mutation in the patients (Bodapati Chandra Mouleshware Prasad, 2018).
Table 2 above shows the gene that underwent mutation and the protein affected in each individual. Protein Kinase C domain in the NFN1 protein was affected in these cases. This domain encodes for amino acids 97-243 (Bodapati Chandra Mouleshware Prasad, 2018).
Genetic analysis of these family showed that in family 1, a novel mutation in c.308G>A (adenine), c.313G>A, c.321G>T, c.336G>A, c.340C>A and c.346G>T led to mutations in proteins p.R103K, p.d105n, p.M108I, p.L114M and p.Glu116X. These proteins were all located at exon 4. Members of family II had a novel mutation at exon 4 c.391G>T. This led to missense mutation which affected protein p.A131S. In a similar light, all three participants in family III experienced variation in exon 7. They had a c.671dub mutation on this exon and this caused novel frame shift in p.E225Rfs*6 and also caused stop codon to be formed prematurely at D229 amino acid. This caused a truncated protein to be formed. The missense mutation also caused a silent variant in exon 7 of protein kinase C domain in the NF1 protein. (Bodapati Chandra Mouleshware Prasad, 2018).
The down-regulator of RAS proteins by mutated neurofibromin protein leads to tumour formation which is often expressed phenotypically in people living with the condition. It often manifests in different ways even among members of the same family (Deborah R. Gold, 2003). This makes genetic counselling difficult as it is difficult to predict how it would occur on the next individual.
Patients with NFN1 are often prone to other ailments such as cancer due to other pathways are affected or inactivated by the mutated genes. Hence further research needs to be carried out to investigate if there are other tumour suppressant gene other than NFN1 gene present and ways to activate these genes in the absence of NFN1 gene.