3pg7

Structural highlights

Disease

[NF1_HUMAN] Defects in NF1 are the cause of neurofibromatosis type 1 (NF1) [MIM:162200]; also known as von Recklinghausen syndrome. A disease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]} Defects in NF1 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Germline mutations of NF1 account for the association of JMML with type 1 neurofibromatosis (NF1). Defects in NF1 are the cause of Watson syndrome (WS) [MIM:193520]. WS is characterized by the presence of pulmonary stenosis, cafe-au-lait spots, and mental retardation. WS is considered as an atypical form of NF1. Defects in NF1 are a cause of familial spinal neurofibromatosis (FSNF) [MIM:162210]. Familial spinal NF is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors.^[30] Defects in NF1 are a cause of neurofibromatosis-Noonan syndrome (NFNS) [MIM:601321]. NFNS is characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis.^{[31] [32] [33]} Defects in NF1 may be a cause of colorectal cancer (CRC) [MIM:114500].

Function

[NF1_HUMAN] Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity.^[34]

References

1. ↑ Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, et al.. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1):193-201. PMID:2114220
2. ↑ Upadhyaya M, Shen M, Cherryson A, Farnham J, Maynard J, Huson SM, Harper PS. Analysis of mutations at the neurofibromatosis 1 (NF1) locus. Hum Mol Genet. 1992 Dec;1(9):735-40. PMID:1302608
3. ↑ Purandare SM, Lanyon WG, Connor JM. Characterisation of inherited and sporadic mutations in neurofibromatosis type-1. Hum Mol Genet. 1994 Jul;3(7):1109-15. PMID:7981679
4. ↑ Abernathy CR, Colman SD, Kousseff BG, Wallace MR. Two NF1 mutations: frameshift in the GAP-related domain, and loss of two codons toward the 3' end of the gene. Hum Mutat. 1994;3(4):347-52. PMID:8081387 doi:http://dx.doi.org/10.1002/humu.1380030404
5. ↑ Upadhyaya M, Maynard J, Osborn M, Huson SM, Ponder M, Ponder BA, Harper PS. Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene. J Med Genet. 1995 Sep;32(9):706-10. PMID:8544190
6. ↑ Gasparini P, D'Agruma L, Pio de Cillis G, Balestrazzi P, Mingarelli R, Zelante L. Scanning the first part of the neurofibromatosis type 1 gene by RNA-SSCP: identification of three novel mutations and of two new polymorphisms. Hum Genet. 1996 Apr;97(4):492-5. PMID:8834249
7. ↑ Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman JJ, Fryns JP. Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat. 1996;8(1):51-6. PMID:8807336 doi:<51::AID-HUMU7>3.0.CO;2-S 10.1002/(SICI)1098-1004(1996)8:1<51::AID-HUMU7>3.0.CO;2-S
8. ↑ Upadhyaya M, Osborn MJ, Maynard J, Kim MR, Tamanoi F, Cooper DN. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1997 Jan;99(1):88-92. PMID:9003501
9. ↑ Maynard J, Krawczak M, Upadhyaya M. Characterization and significance of nine novel mutations in exon 16 of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1997 May;99(5):674-6. PMID:9150739
10. ↑ Hudson J, Wu CL, Tassabehji M, Summers EM, Simon S, Super M, Donnai D, Thakker N. Novel and recurrent mutations in the neurofibromatosis type 1 (NF1) gene. Hum Mutat. 1997;9(4):366-7. PMID:9101300 doi:<366::AID-HUMU12>3.0.CO;2-0 10.1002/(SICI)1098-1004(1997)9:4<366::AID-HUMU12>3.0.CO;2-0
11. ↑ Upadhyaya M, Maynard J, Osborn M, Harper PS. Six novel mutations in the neurofibromatosis type 1 (NF1) gene. Hum Mutat. 1997;10(3):248-50. PMID:9298829 doi:<248::AID-HUMU14>3.0.CO;2-# 10.1002/(SICI)1098-1004(1997)10:3<248::AID-HUMU14>3.0.CO;2-#
12. ↑ Klose A, Ahmadian MR, Schuelke M, Scheffzek K, Hoffmeyer S, Gewies A, Schmitz F, Kaufmann D, Peters H, Wittinghofer A, Nurnberg P. Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum Mol Genet. 1998 Aug;7(8):1261-8. PMID:9668168
13. ↑ Krkljus S, Abernathy CR, Johnson JS, Williams CA, Driscoll DJ, Zori R, Stalker HJ, Rasmussen SA, Collins FS, Kousseff BG, Baumbach L, Wallace MR. Analysis of CpG C-to-T mutations in neurofibromatosis type 1. Mutations in brief no. 129. Online. Hum Mutat. 1998;11(5):411. PMID:10336779 doi:<411::AID-HUMU11>3.0.CO;2-2 10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU11>3.0.CO;2-2
14. ↑ Messiaen LM, Callens T, Roux KJ, Mortier GR, De Paepe A, Abramowicz M, Pericak-Vance MA, Vance JM, Wallace MR. Exon 10b of the NF1 gene represents a mutational hotspot and harbors a recurrent missense mutation Y489C associated with aberrant splicing. Genet Med. 1999 Sep-Oct;1(6):248-53. PMID:11258625
15. ↑ Peters H, Hess D, Fahsold R, Schulke M. A novel mutation L1425P in the GAP-region of the NF1 gene detected by temperature gradient gel electrophoresis (TGGE). Mutation in brief no. 230. Online. Hum Mutat. 1999;13(4):337. PMID:10220149 doi:<337::AID-HUMU13>3.0.CO;2-C 10.1002/(SICI)1098-1004(1999)13:4<337::AID-HUMU13>3.0.CO;2-C
16. ↑ Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kucukceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nurnberg P. 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. 2000 Mar;66(3):790-818. PMID:10712197 doi:10.1086/302809
17. ↑ Ars E, Serra E, Garcia J, Kruyer H, Gaona A, Lazaro C, Estivill X. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet. 2000 Jan 22;9(2):237-47. PMID:10607834
18. ↑ Girodon-Boulandet E, Pantel J, Cazeneuve C, Gijn MV, Vidaud D, Lemay S, Martin J, Zeller J, Revuz J, Goossens M, Amselem S, Wolkenstein P. NF1 gene analysis focused on CpG-rich exons in a cohort of 93 patients with neurofibromatosis type 1. Hum Mutat. 2000 Sep;16(3):274-5. PMID:10980545
19. ↑ Han SS, Cooper DN, Upadhyaya MN. Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1) gene. Hum Genet. 2001 Nov;109(5):487-97. Epub 2001 Oct 11. PMID:11735023 doi:10.1007/s004390100594
20. ↑ Kluwe L, Friedrich RE, Korf B, Fahsold R, Mautner VF. NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas. Hum Mutat. 2002 Mar;19(3):309. PMID:11857752 doi:10.1002/humu.9018
21. ↑ Wang Q, Montmain G, Ruano E, Upadhyaya M, Dudley S, Liskay RM, Thibodeau SN, Puisieux A. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet. 2003 Feb;112(2):117-23. Epub 2002 Nov 21. PMID:12522551 doi:10.1007/s00439-002-0858-4
22. ↑ De Luca A, Buccino A, Gianni D, Mangino M, Giustini S, Richetta A, Divona L, Calvieri S, Mingarelli R, Dallapiccola B. NF1 gene analysis based on DHPLC. Hum Mutat. 2003 Feb;21(2):171-2. PMID:12552569 doi:10.1002/humu.9111
23. ↑ Kluwe L, Tatagiba M, Funsterer C, Mautner VF. NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet. 2003 May;40(5):368-71. PMID:12746402
24. ↑ Zatkova A, Messiaen L, Vandenbroucke I, Wieser R, Fonatsch C, Krainer AR, Wimmer K. Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1. Hum Mutat. 2004 Dec;24(6):491-501. PMID:15523642 doi:10.1002/humu.20103
25. ↑ De Luca A, Schirinzi A, Buccino A, Bottillo I, Sinibaldi L, Torrente I, Ciavarella A, Dottorini T, Porciello R, Giustini S, Calvieri S, Dallapiccola B. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. PMID:15146469 doi:10.1002/humu.9245
26. ↑ Mattocks C, Baralle D, Tarpey P, ffrench-Constant C, Bobrow M, Whittaker J. 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. 2004 Apr;41(4):e48. PMID:15060124
27. ↑ Ferner RE, Hughes RA, Hall SM, Upadhyaya M, Johnson MR. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet. 2004 Nov;41(11):837-41. PMID:15520408 doi:10.1136/jmg.2004.021683
28. ↑ Bertola DR, Pereira AC, Passetti F, de Oliveira PS, Messiaen L, Gelb BD, Kim CA, Krieger JE. Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A. 2005 Jul 30;136(3):242-5. PMID:15948193 doi:10.1002/ajmg.a.30813
29. ↑ Ponti G, Losi L, Martorana D, Priola M, Boni E, Pollio A, Neri TM, Seidenari S. Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas. Hered Cancer Clin Pract. 2011 Aug 12;9:6. doi: 10.1186/1897-4287-9-6. PMID:21838856 doi:10.1186/1897-4287-9-6
30. ↑ Kaufmann D, Muller R, Bartelt B, Wolf M, Kunzi-Rapp K, Hanemann CO, Fahsold R, Hein C, Vogel W, Assum G. Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene. Am J Hum Genet. 2001 Dec;69(6):1395-400. Epub 2001 Oct 18. PMID:11704931 doi:S0002-9297(07)61269-5
31. ↑ Baralle D, Mattocks C, Kalidas K, Elmslie F, Whittaker J, Lees M, Ragge N, Patton MA, Winter RM, ffrench-Constant C. Different mutations in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS). Am J Med Genet A. 2003 May 15;119A(1):1-8. PMID:12707950 doi:10.1002/ajmg.a.20023
32. ↑ De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet. 2005 Dec;77(6):1092-101. Epub 2005 Oct 26. PMID:16380919 doi:S0002-9297(07)63392-8
33. ↑ Nystrom AM, Ekvall S, Allanson J, Edeby C, Elinder M, Holmstrom G, Bondeson ML, Anneren G. Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1. Clin Genet. 2009 Dec;76(6):524-34. doi: 10.1111/j.1399-0004.2009.01233.x. Epub, 2009 Oct 21. PMID:19845691 doi:10.1111/j.1399-0004.2009.01233.x
34. ↑ Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990 Nov 16;63(4):851-9. PMID:2121371
35. ↑ Welti S, Kuhn S, D'Angelo I, Bruugger B, Kaufmann D, Scheffzek K. Structural and biochemical consequences of NF1 associated non-truncating mutations in the Sec14-PH module of neurofibromin. Hum Mutat. 2010 Nov 18. PMID:21089070 doi:10.1002/humu.21405