Identification Of Mutations Of The NF1 Gene In Two Chinese Patients With Neurofibromatosis Type 1

Background Neurofibromatosis type 1(NF1,von Recklinghausen neurofibromatosis, OMIM 162200) is a common autosomal dominant disorder.The estimated incidence is 5/100 000 per year in westem populations.About 20%～60%of the cases are family and they are more commonly found in females.NF1 is clinically characterized by cutaneous neurofibromas,cafe'-au-lait spots,iris hamartomas(Lisch nodules), malignantperipheral nerve sheath tumor,skeletal anomalies,learning disabilities,and so on.Approximately 15.0%～19.87%patients accompany central nervous system tumors. NF1 gene is maped on chromosome 17q11.2 and cloned in1990.At present it is mainly taken place by the NF1 gene mutation.Approximately 50%of the reported cases represent new family mutations,To date,a total of 728 mutations in the NF1 gene have been recorded on The Human Gene Mutation Database.The types of mutations in the NF1 gene are missense/nonsense,Splicing,regulatory,small deletion,small insertion, small indel,gross deletion,gross insertion,complex,repeat mutations and most mutations could cause truncation protein.NF1 is considered to be a tumor-suppressor gene,it mainly negatively regulates ras signal pathway by the GTPase-activating protein(GAP) of NF1 gene transcript called ne urofibromin,and regulates mTOR pathway and controls the level of cAMP/AC,participates the growth and differentiation of cell and tumor formation.Although most researches on NF1 gene mutations were carried out at home and abroad,the genotype/phenotype correlations are still unknown.Objective To identify NF1 gene mutations in two Chinese patients with NF1.This study will contribute to expand database of NF1 gene and further illustrate the extensive diversity of mutational events.that led to the different phenotypes of NF1. Methods We collected two Chinese NF1 patients and their blood samples and 100 unrelated population-matched controls.Genomic DNA was extracted from peripheral blood.All the coding exons of NF1 gene were amplified by polymerase chain reaction and products analyzed by direct sequencing.Results We identified two novel mutations in two NF1 patients,including a nonsense mutation c.1009G＞T and a small deletion mutation c.3443₃444delCA.The nonsense mutation c.1009G＞T caused the 337^th coden GAA is replaced by TAA(premature termination codon) in the eoxn 7 of the patient 1 and the amino acid translation terminated,then the reverse sequencing result confirmed it,The deletion mutation c.3443₃444delCA caused sequence frameshift and premature termination codon TGA in the 3579^th in the exon 21 of patient 2.but the two mutations were not found in 100 unrelated population-matched control individuals.Two mutations in NF1 gene were first reported at home and abroad and the two mutations are not rare single nucleotide polymerphisms(SNPs)Conclusions The nonsense mutation c.1009G＞T and the small deletion,mutation c.3443₃444delCA in NF1 gene are the cause of clinical phenotype of the two cases with neurofibromatosis type 1...