Abstract
Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders in humans, and presents with a variety of clinical symptoms, which are highly variable in expression. The mutation rate for NF1 is high, with as many as half of all cases resulting from new mutations. Although the NF1 gene has been cloned and its cDNA sequence determined, the specific role of the NF1 gene product in contributing to the NF1 phenotype has not been clarified. The characterization of NF1 mutations is one of the first steps in correlating genotype with clinical symptoms of the disease. In this paper we describe two independent mutations in exon 31 of the NF1 gene identified following polymerase chain reaction (PCR) amplification, heteroduplexing, and single strand conformational polymorphism (SSCP) analysis. One is a novel insertion that segregates with the disease phenotype in that particular family (5852insTT), while the other is a further example of the sporadic, recurrent C→T mutation previously described in the literature (C5842T). The relationship between these mutations and clinical features of NF1 presented by the patients will be discussed.
Similar content being viewed by others
References
Ainsworth PJ, Surh LC, Coulter-Mackie MB (1991) Diagnostic single strand conformational polymorphism (SSCP): a simplified non-radioisotopic method as applied to a Tay-Sachs B1 variant. Nucleic Acids Res 19:405–406
Andersson A, Johansson J (1987) Rapid purity checking of synthetic oligonucleotides with PhastSystemTM. J Biochem Biophys Methods 14 [Suppl]:37
Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213
Cawthon RW, Weiss R, Xu G, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, White R (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62:193–203
Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155
Estivill X, Lazaro C, Casals T, Ravella A (1991) Recurrence of a nonsense mutation in the NF1 gene causing classical neurofibromatosis type 1. Hum Genet 88:185–188
Hall JG, Allanson JE (1991) Neurofibromatosis I: predicting the relation of gene structure to gene function. Am J Med Genet 38:135
Huson SM, Compston DAS, Clark P, Harper PS (1989) A genetic study of von Recklinghausen neurofibromatosis in southeast Wales. I. Prevalence, fitness, mutation rate, and the effect of parental transmission on severity. J Med Genet 26:704–711
Jadayel D, Fain P, Upadyaya M, Ponder MA, Huson SM, Carey J, Fryer A, Mathew CGP, Barker DF, Ponder BAJ (1990) Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 343:558–559
Li Y, Bollag G, Clark R, Stevens J, Conroy L, Fults D, Friedman E, Samowitz W, Robertson M, Bradley P, McCormick F, White R, Cawthon RW (1992) Somatic mutations in the neurofibromatosis 1 gene in human tumours. Cell 69:275–281
Marchuk DA, Saulino AM, Tavakkol R, Swaroop M, Wallace MR, Andersen LB, Mitchell AL, Gutmann DH, Boguski M, Collins FS (1991) cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11:931–940
Orita M, Suzuki Y, Takao S, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874–879
Orita M, Seyika T, Hayashi K (1990) DNA sequence polymorphisms in Alu repeats. Genomics 8:271–278
Riccardi VM, Eichner JE (1986) Neurofibromatosis: phenotype, natural history and pathogenesis. Johns Hopkins University Press, Baltimore
Rodenhiser DI, Coulter-Mackie MB, Jung JH, Singh SM (1991) A genetic study of neurofibromatosis 1 in southwestern Ontario. I. Population, familial segregation of phenotype and molecular linkage. J Med Genet 28:746–751
Rommens J, Kerem BS, Greer W, Chang P, Tsui L-C, Ray P (1990) Rapid non-radioactive detection of the major cystic fibrosis mutation. Am J Hum Genet 46:395–396
Rubenstein AE, Korf BR (1990) Neurofibromatosis: a handbook for patients, families and health-care professionals. Thieme, Stuttgart New York
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Sanger F, Nicklen S, Coulsen AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Stark M, Assum G, Krone W (1991) A small deletion and an adjacent base exchange in a potential stem-loop region of the neurofibromatosis 1 gene. Hum Genet 87:685–687
Stephens K, Kayes L, Riccardi VM, Rising M, Sybert VP, Pagon RA (1992) Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet 88:279–282
Stumpf DA, Alksne JF, Annegers JF, et al (1988) Neurofibromatosis. Arch Neurol 45:575–578
Viskochil D, Buchberg AM, Xu G, Cawthon RW, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O'Connell P (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62:187–192
Wallace MR, Marchuk DA, Andersen LB, Lethcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, Brownstein BH, Collins FS (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186
Xu G, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, Weiss R (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ainsworth, P.J., Rodenhiser, D.I. & Costa, M.T. Identification and characterization of sporadic and inherited mutations in exon 31 of the neurofibromatosis (NF1) gene. Hum Genet 91, 151–156 (1993). https://doi.org/10.1007/BF00222716
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00222716