Abstract
Neurofibromatosis type 1 (NF1) is one of the most common inherited human disorders, with an estimated incidence of 1 per 3500 births. In most cases, the disease is caused either by mutation in the NF1 gene, or by a particular or complete deletion of the NF1 gene. The NF1 gene exhibits one of the highest mutation rates of any human disorder. In this experimental study of the NF1 gene, we screened the mutational spectrum of 22 unrelated patients from the Czech Republic using the denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) methods. We found NF1 mutations in 17 patients: 15 causal mutations were detected with the use of the DHPLC method (15/20, 75%). With the MPLA method, we also confirmed and specified two large deletions that were previously genotyped by microsatellite markers. Twelve of the above mentioned mutations were newly found:c.1_2delATinsCC, c.1185+1G>C, c.1757_1760delCTAG, c.1642-7A>G, c.2329 T>G, c.2816delA, c.3738_3741delGTTT, c.4733 C>T, c.5220delT, c.6473_6474insGAAG, ex 14_49del, ex28_49del. We present this study as a first effectual step in the routine diagnosis of the NF1 in patients from the Czech Republic.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahmadian M. R., Kiel C., Stege P., and Scheffzek K. (2003) Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP. J. Mol. Biol. 329, 699–710.
Ars E., Kruyer H., Morell M., et al. (2003) Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J. Med. Genet. 40, e82.
De Luca A., Schirinzi A., Buccino A., et al. (2004) Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum. Mutat. 23, 629.
Donohoe E. (2005) Denaturing high-performance liquid chromatography using the WAVE DNA fragment analysis system. Methods Mol. Med. 108, 173–187.
Fahsold R., Hoffmeyer S., Mischung C., et al. (2000) Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am. J. Hum. Genet. 66, 790–818.
Gutmann D. H., Aylsworth A., Carey J. C., et al. (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278, 51–57.
Han S. S., Cooper D. N., and Upadhyaya M. N. (2001) Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 (NF1) gene. Hum. Genet. 109, 487–497.
Jeong S. Y., Park S. J., and Kim H. J. (2006) The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J. Korean Med. Sci. 21, 107–112.
Kluwe L., Friedrich R. E., Peiper M., Friedman J., and Mautner V.F. (2003) Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. Hum. Mutat. 22, 420.
Kuklin A., Munson K., Gjerde D., Haefele R., and Taylor P. (1997) Detection of single-nucleotide polymorphisms with the WAVE DNA fragment analysis system. Genet. Test. 1, 201–206.
Lazaro C., Gaona A., Xu G., Weiss R., and Estivill X. (1993) A highly informative CA/GT repeat polymorphism in intron 38 of the human neurofibromatosis type 1 (NF1) gene. Hum. Genet. 92, 429–430.
Lazaro C., Gaona A., and Estivill X. (1994) Two CA/GT repeat polymorphisms in intron 27 of the human neurofibromatosis (NF1) gene. Hum. Genet. 93, 351–352.
Lee M. J., Su Y. N., You H. L., et al. (2006) Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum. Mutat. 27, 832.
Mattocks C., Baralle D., Tarpey P., ffrench-Constant C., Bobrow M., and Whittaker J. (2004) Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11–17 distinct from the GAP related domain. J. Med. Genet. 41, e48.
Scheffzek K., Ahmadian M. R., Wiesmuller L., et al. (1998) Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J. 17, 4313–4327.
Schouten J. P., McElgunn C. J., Waaijer R., Zwijnenburg D., Diepvens F., and Pals G. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57.
Side L., Taylor B., Cayouette M., et al. (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N. Engl. J. Med. 336, 1713–1720.
Tonsgard J. H. (2006) Clinical manifestations and management of neurofibromatosis type 1. Semin. Pediatr. Neurol. 13, 2–7.
Upadhyaya M., Maynard J., Osborn M., et al. (1995) Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene. J. Med. Genet. 32, 706–710.
Wimmer K., Yao S., Claes K., et al. (2006) Spectrum of single-and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer 45, 265–276.
(1988) Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 45, 575–578.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bendova, S., Krepelova, A., Petrak, B. et al. Novel mutations in the NF1 gene in Czech patients with neurofibromatosis type 1. J Mol Neurosci 31, 273–279 (2007). https://doi.org/10.1385/JMN:31:03:273
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:31:03:273