Molecular Genetics for the Taiwanese Patients with Neurofibromatosis,type I

Neurofibromatosis type 1 (NF1; MIM# 162200) is a common autosomal dominant disorder, affecting approximately one is every 4000 individuals. NF1 is also one of the most common single-gene disorders influencing neurological function in humans. Neurofibromatosis type1 (NF1) is caused by the mutation of NF1 gene which encoded a 2818 aminocaid protein, neurofibromin. Neurofibromin, harboring a GTP binding domain, interferes with the signal transduction of RAS-ERK-MAPK pathway. The NF1 gene is located at chromosome 17q11.2 and spans approximately 350 kb genomic DNA. he clinical features of the disease include café-au-lait spots, iris harmatomas (Lisch nodules), and freckling of axillary and inguinal regions. The features are presented in most of the patients after puberty. Some less frequent, nevertheless with more severe manifestations, such as deeply situated and arbitrarily located neurofibromas, plexiform neurofibromas, macrocephaly, optic glioma, short stature, learning difficulties with mild retardation, scoliosis, pseudoarthrosis and even certain malignancies occur among patients with NF1. p to date, five hundred different mutations have been reported, including deletion, insertion, frameshift mutations, missense mutations, nonsense mutations, splicing mutations. However, not any a report demonstrated the genotype of the NF1 mutation in Chinese patients with NF1. The aim of this study is to use the DHPLC to screen the NF1 gene mutation in Taiwanese patients with NF1. he patients were recruited from the Department of Medical Genetics National Taiwan University Hospital or been transfer from other Hospital. In total, samples from 107 NF1 patients were collected. The DHPLC screening identified 58 heteroduplex with further sequencing confirmed. Five small molecular defects, which were not detected by DHPLC, were identified by direct sequencing. The genotypes for the Taiwanese/Chinese NF1 patientsomposed of missense mutation 11(16.25%), 20 (29.4%) of nonsense mutation, 23 (33.8%) framshift and 9 splicing or intron mutation. To screen the large deletion which involving the whole gene, two methods, loss-of-heterozygosity and quantitative PCR were employed. Loss of heterozygosity with reduced genomic DNA copy number were identified in 5 patients. Thus, using a serial mutation identification methodology, we found 68 mutations in 107 NF1 patients. The detection rate is 64%. kin manifestion, café-au-lait spots, occurs in all the NF1 patients (68/68, 100%). The cutaneous neurofibromas were found in 79.4% patients (54/68). Forty-one patients had freckling at axillary and inguinal regions (41/68, 60.3%). Nearly, one-fourths patients had plexiform neurofibroma (19/68, 27.9%). Some less frequent, nevertheless with more severe manifestations. ccording to this study, no phenotype -genotype correlation is identified. Both the NF1 phenotype and genotype are highly variable. Patients harbor a NF1 gene mutation always show the NF1 features. The mutation detection rate is not high enough. Thus, the more cost-effective and energy-saving methods to improve the genetic diagnosis is important in the future. In addition, studies on the functional implications and pathogenesis for the NF1 mutation would be the cornerstone to shed light on the treatment strategy.