Neurofibromin protein consists of 2839 amino acids and weighs about 319 kDa. It is produced in many cell types, such as nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves. It acts as a tumor suppressor protein and function as a negative regulator by turning off RAS protein that stimulates cell growth and division; thereby, preventing cell overgrowth. Defects in neurofibromin protein cause an autosomal dominant condition called neurofibromatosis type I (NF1), characterized by cafe-au-lait spots, axillary freckling, Lisch nodules of the iris, multiple neurofibromas, tibial pseudarthrosis and a predisposition to certain benign and malignant tumors of the central and peripheral nervous system.
The neurofibromin 1 (NF1) gene is located at chromosome 17q11.2, where it spans a length of about 287 kb of genomic DNA, and contains 58 exons. Several mutations have been identified in this gene causing neurofibromatosis type 1. Many of these mutations result in a truncated protein while some of them cause amino acid substitutions. The mutated protein cannot perform its normal job of inhibiting cell division, causing loss of neurofibromin, which allows noncancerous tumors called neurofibromas to form.
A novel frameshift mutation (c.7317delA) in an Iraqi child, living in the United Arab Emirates, with Neurofibromatosis type 1 has been identified in the NF1 gene by Al-Gazali et al. (2010).
Alkindy et al. (2012) evaluated the clinical phenotype associated with the specific types of NF1 mutation in a retrospectively recorded clinical dataset comprising 149 NF1 mutation-known individuals from unrelated families. Patients were subcategorized according to their associated NF1 germ line mutations: frame shift deletions (52; including: c.495delTGTT, c.3721-3722insA, c.5406insT, c.6219delT, c.6403insGA, c.6791insA, c.7892-7893delAA), splice-site mutations (23; including: c.589-2A>G), nonsense mutations (36; including p.R416X, p.R461X, p.K1517X, p.R1748X), missense mutations (32; including: p.W837R, p.M1149I, p.F1193C, p.K1423E, p.L1812P, p.W1931R) and other types of mutation (6). A significant association was apparent between possession of a splice-site mutation and the presence of brain gliomas and MPNSTs (p=0.006).
[See: Iraq > Al-Gazali et al., 2010].
Ben-Salem et al. (2013) studied 12 neurofibromatosis type I patients, of which 7 belonged to 4 different families and 5 were sporadic cases. Genetic analysis of the cohort helped unveil 9 heterozygous mutations in the NF1 gene. These included a large novel 9.2 kb deletion in three members of a family, a novel missense mutation (c.6374T>C, p.Leu2125Pro) in two members of another family, and a novel frameshift (c.1846delC, p.Gln616ArgfsX15) in another family. Sporadic mutations included 3 novel frameshift mutations (c.4065_4066delAG, p.Glu1356IlefsX17; c.5346delT, p.Ile1782MetfsX60; c.3291delA, p.Ala1098ProfsX14), a known nonsense mutation (c.6546C>G, p.Tyr2182X), a known missense mutation (c.2540T>C, p.Leu847Pro) and a known splice site mutation (c.1062+2T>C). Both missense mutations found in the study occurred at highly conserved residues and were predicted by in-silico analysis to be pathogenic. It was noted that no obvious genotype-phenotype correlations were observed in the cohort. Also, the analysis indicated the absence of hotspots in the NF1 gene.
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