6ob2

Structural highlights

Disease

[RASK_HUMAN] Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.^[1] Defects in KRAS 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. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor. Defects in KRAS are the cause of Noonan syndrome type 3 (NS3) [MIM:609942]. Noonan syndrome (NS) [MIM:163950] is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS3 inheritance is autosomal dominant.^{[2] [3] [4] [5] [6] [7]} Defects in KRAS are a cause of gastric cancer (GASC) [MIM:613659]; also called gastric cancer intestinal or stomach cancer. Gastric cancer is a malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.^{[8] [9] [10]} Note=Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.^[11] Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note=KRAS mutations are involved in cancer development. [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.^{[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40]} 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.^[41] 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.^{[42] [43] [44]} Defects in NF1 may be a cause of colorectal cancer (CRC) [MIM:114500].

Function

[RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. [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.^[45]

References

1. ↑ Bollag G, Adler F, elMasry N, McCabe PC, Conner E Jr, Thompson P, McCormick F, Shannon K. Biochemical characterization of a novel KRAS insertion mutation from a human leukemia. J Biol Chem. 1996 Dec 20;271(51):32491-4. PMID:8955068
2. ↑ Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, Digilio C, Palleschi A, Pizzuti A, Grammatico P, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. 2006 Jul;79(1):129-35. Epub 2006 May 1. PMID:16773572 doi:10.1086/504394
3. ↑ Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar;38(3):331-6. Epub 2006 Feb 12. PMID:16474405 doi:ng1748
4. ↑ Bertola DR, Pereira AC, Brasil AS, Albano LM, Kim CA, Krieger JE. Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene. J Hum Genet. 2007;52(6):521-6. Epub 2007 Apr 28. PMID:17468812 doi:10.1007/s10038-007-0146-1
5. ↑ Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007 Feb;44(2):131-5. Epub 2006 Oct 20. PMID:17056636 doi:10.1136/jmg.2006.046300
6. ↑ Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, Oudesluys-Murphy AM, Di Rocco C, Kloska SP, Tartaglia M, Zenker M. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. Am J Med Genet A. 2009 May;149A(5):1036-40. doi: 10.1002/ajmg.a.32786. PMID:19396835 doi:10.1002/ajmg.a.32786
7. ↑ Gremer L, Merbitz-Zahradnik T, Dvorsky R, Cirstea IC, Kratz CP, Zenker M, Wittinghofer A, Ahmadian MR. Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Hum Mutat. 2011 Jan;32(1):33-43. doi: 10.1002/humu.21377. Epub 2010 Dec 9. PMID:20949621 doi:10.1002/humu.21377
8. ↑ Deng GR, Lu YY, Chen SM, Miao J, Lu GR, Li H, Cai H, Xu XL, E Z, Liu PN. Activated c-Ha-ras oncogene with a guanine to thymine transversion at the twelfth codon in a human stomach cancer cell line. Cancer Res. 1987 Jun 15;47(12):3195-8. PMID:3034404
9. ↑ Lee KH, Lee JS, Suh C, Kim SW, Kim SB, Lee JH, Lee MS, Park MY, Sun HS, Kim SH. Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases. Cancer. 1995 Jun 15;75(12):2794-801. PMID:7773929
10. ↑ Lee SH, Lee JW, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Nam SW, Kim SH, Lee JY, Yoo NJ. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003 Oct 9;22(44):6942-5. PMID:14534542 doi:10.1038/sj.onc.1206749
11. ↑ Motojima K, Urano T, Nagata Y, Shiku H, Tsurifune T, Kanematsu T. Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma. Ann Surg. 1993 Feb;217(2):138-43. PMID:8439212
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ 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
19. ↑ 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
20. ↑ 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
21. ↑ 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
22. ↑ 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-#
23. ↑ 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
24. ↑ 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
25. ↑ 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
26. ↑ 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
27. ↑ 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
28. ↑ 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
29. ↑ 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
30. ↑ 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
31. ↑ 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
32. ↑ 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
33. ↑ 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
34. ↑ 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
35. ↑ 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
36. ↑ 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
37. ↑ 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
38. ↑ 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
39. ↑ 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
40. ↑ 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
41. ↑ 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
42. ↑ 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
43. ↑ 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
44. ↑ 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
45. ↑ 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