The mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAE
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Germline heterozygous mutations in the tumor suppresser NF1 gene cause a cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This disease is one of the most common multisystem disorders with an estimated incidence of 1 in 3,000 to 1 in 4,000 births. Clinically, NF1 patients are prone to develop “café au lait” spots, neurofibromas, Lisch nodules, freckling of the axillary, or inguinal region and optic nerve gliomas.
Materials and methods
In the present study, we report clinical and molecular findings of five unrelated patients and seven cases from four families with NF1 from UAE. To reveal the genetic defects underlying NF1 in our cohort of patients, we screened the whole coding and splice site regions of the NF1 gene. In addition, MLPA or CGH array has been used to screen for structural variations including deletions, indels, and complex rearrangements.
This resulted in the identification of five distinct novel mutations and two previously reported ones. These variations included three missense and one nonsense mutations, one single base, one dinucleotide, and one large deletion.
Four mutations were inherited, and the remaining were absent from both parents and therefore are “de novo” mutations. This analysis represents the spectrum of NF1 mutations in UAE and supports the premise of absence of hotspot mutations in the NF1 gene. Moreover, no obvious genotype-phenotype correlations were observed in our patients.
KeywordsNeurofibromatosis type 1 von Recklinghausen NF1 “de novo” mutations
We are thankful for patients and their family members for their participation in this research study. The laboratories of L.A. and B.R.A. are funded by the United Arab Emirates University.
Conflict of interest
All authors have declared that no competing interests exist.
- 1.Raphael R, Strayer DS (2008) Rubin's pathology: clinicopathologic foundation of medicine. Wolters Kluwer Health: Lippincot Williams & Wilkins, BaltimoreGoogle Scholar
- 7.(1988) Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 45: 575–578Google Scholar
- 10.Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kücükceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nürnberg P (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 66:790–818PubMedCentralPubMedCrossRefGoogle Scholar
- 11.Korf BR, Rubenstein AE (2005) Neurofibromatosis: a handbook for families, patients and health care professionals. Thieme, New YorkGoogle Scholar
- 16.Trovó-Marqui AB, Goloni-Bertollo EM, Valério NI, Pavarino-Bertelli EC, Muniz MP, Teixeira MF, Antonio JR, Tajara EH (2005) High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. Braz J Med Biol Res 38:1441–1447PubMedCrossRefGoogle Scholar
- 19.Steinemann D, Arning L, Praulich I, Stuhrmann M, Hasle H, Stary J, Schlegelberger B, Niemeyer CM, Flotho C (2010) Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1. Haematologica 95:320–323PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Gug C, Anghel A, Tamas L, Seclaman E, Willems P (2010) Neurofibromatosis type 1—molecular testing and clinical presentation of two cases. Annals of the “Alaxendru Iaon Cuza” University SectIIa. Genet Mol Biol 11:33–38Google Scholar
- 30.Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7: Unit7.20Google Scholar
- 37.Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN (1998) Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet 102:591–597PubMedCrossRefGoogle Scholar
- 38.Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P, Vidaud D, Wolkenstein P, Network motNF (2009) Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet 18:2768–2778PubMedCentralPubMedCrossRefGoogle Scholar
- 40.Bausch B, Borozdin W, Mautner VF, Hoffmann MM, Boehm D, Robledo M, Cascon A, Harenberg T, Schiavi F, Pawlu C, Peczkowska M, Letizia C, Calvieri S, Arnaldi G, Klingenberg-Noftz RD, Reisch N, Fassina A, Brunaud L, Walter MA, Mannelli M, MacGregor G, Palazzo FF, Barontini M, Walz MK, Kremens B, Brabant G, Pfäffle R, Koschker AC, Lohoefner F, Mohaupt M, Gimm O, Jarzab B, McWhinney SR, Opocher G, Januszewicz A, Kohlhase J, Eng C, Neumann HP, Group E-APRS (2007) Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. J Clin Endocrinol Metab 92:2784–2792PubMedCrossRefGoogle Scholar
- 48.Patrakitkomjorn S, Kobayashi D, Morikawa T, Wilson MM, Tsubota N, Irie A, Ozawa T, Aoki M, Arimura N, Kaibuchi K, Saya H, Araki N (2008) Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2. J Biol Chem 283:9399–9413PubMedCrossRefGoogle Scholar
- 49.Yunoue S, Tokuo H, Fukunaga K, Feng L, Ozawa T, Nishi T, Kikuchi A, Hattori S, Kuratsu J, Saya H, Araki N (2003) Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. J Biol Chem 278:26958–26969PubMedCrossRefGoogle Scholar