Abstract
Purpose
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an estimated incidence of one in 3,500 births. Clinically, NF1 is characterized by café-au-lait (CAL) spots, neurofibromas, freckling of the axillary or inguinal region, Lisch nodules, optic nerve glioma, and bone dysplasias. NF1 is caused by inactivating mutations of the 17q11.2-located NF1 gene. We present a clinical and molecular study of an Italian family with NF1.
Methods
The proband, a 10-year-old boy, showed large CAL spots and freckling on the axillary region and plexiform neurofibromas on the right side only. His father (47 years old) showed, in addition to the similar signs, numerous neurofibromas of various sizes on his thorax, abdomen, back, and shoulder. Two additional family members (a brother and a sister of the proband) presented only small CAL spots. The coding exons of NF1 gene were analyzed for mutations by denaturing high-performance liquid chromatography and sequencing in all family members.
Results
The mutational analysis of the NF1 gene revealed a novel frameshift insertion mutation in exon 4c (c.654 ins A) in all affected family members. This novel mutation creates a shift on the reading frame starting at codon 218 and leads to the introduction of a premature stop at codon 227.
Conclusions
The segregation of the mutation with the affected phenotype and its absence in the 200 normal chromosomes suggest that it is responsible for the NF1 phenotype.
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References
OMIM™. Online Mendelian Inheritance in Men™ (2004) McKusick catalog of human genes. Johns Hopkins University Library. Johns Hopkins University Press, Baltimore, http://www.ncbi.nlm.nih.gov/omim
Li Y, O’Connell P, Breidenbach HH, Cawthon R, Stevens J, Xu G, Neil S, Robertson M, White R, Viskochil D (1995) Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 25:9–18
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
Xu GF, O’Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608
Scheffzek K, Ahmadian MR, Wiesmuller L, Kabsch W, Stege P, Schmitz F, Wittinghofer A (1998) Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J 17:4313–4327
Ahmadian MR, Kiel C, Stege P, Scheffzek K (2003) Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP. J Mol Biol 329:699–710
Mattocks C, Baralle D, Tarpey P, Frenc-Constant C, Bobrow M, 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
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57
Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A (2007) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44(2):81–88
Riccardi VM (1993) Genotype, malleotype, phenotype, and randomness: lessons from neurofibromatosis-1 (NF-1). Am J Hum Genet 53:301–304
Easton DF, Ponder MA, Huson SM, Ponder BA (1993) An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet 53:305–313
Wiest V, Eisenbarth I, Schmegner C, Krone W, Assum G (2003) Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers. Hum Mutat 22:423–427
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Han S, Cooper DN, Upadhyaya M (2001) Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of neurofibromatosis type1 (NF1) gene. Hum Genet 109:487–497
Xiao W, Oefner P (2001) Denaturing high-performance liquid chromatography: a review. Hum Genet 17:439–474
Korf BR (1992) Diagnostic outcome in children with multiple cafè au lait spots. Pediatrics 90:924–927
Kayes LM, Burke W, Riccardi VM, Bennett R, Ehrlich P, Rubenstein A, Stephens K (1994) Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients. Am J Hum Genet 54:424–436
Wu BL, Austin MA, Schneider GH, Boles RG, Korf BR (1995) Deletion of the entire NF1 gene detected by the FISH: four deletion patients associated with severe manifestations. Am J Med Genet 59:528–535
Leppig KA, Kaplan P, Viskochil D, Weaver M, Ortenberg J, Stephens K (1997) Familial neurofibromatosis 1 microdeletions: cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata. Am J Med Genet 73:197–204
Wu BL, Boles RG, Yaari H, Weremowicz S, Schneider GH, Korf BR (1997) Somatic mosaicism for deletion of the entire NF1 gene identified by FISH. Hum Genet 99(2):209–213
Toliat MR, Erdogan F, Gewies A, Fahsold R, Buske A, Tinschert S, Nurnberg P (2000) Electrophoresis 21:541–544
Griffiths S, Thompson P, Frayling I, Upadhyaya M (2007) Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer 6(1):21–34
Jeong SY, Park SJ, Kim HJ (2006) The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci 21:107–112
Kebudi R, Tuncer S, Upadhyaya M, Peksayar G, Spurlock G, Yazici H (2008) A novel mutation in the NF1 gene in two siblings with neurofibromatosis type 1 and bilateral pathway glioma. Pediatr Blood Cancer 50:713–715
Inoue K, Khajavi M, Ohyama T, Hirabayashi S, Wilson J, Reggin JD et al (2004) Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 36(4):361–369, Electronic publication 2004 Mar 7
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Gabriele, A.L., Ruggieri, M., Patitucci, A. et al. A novel NF1 gene mutation in an Italian family with neurofibromatosis type 1. Childs Nerv Syst 27, 635–638 (2011). https://doi.org/10.1007/s00381-010-1282-z
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DOI: https://doi.org/10.1007/s00381-010-1282-z