Neurofibromatosis type 1 (NF1) is a relatively common genetic disease that increases the chance to develop a variety of benign and malignant tumors. People with NF1 also typically feature a large number of birthmarks called café-au-lait macules. It is difficult to predict severity or specific problems in NF1. We sought to identify genes (other than NF1, the gene that causes the disease) that influence severity in NF1. We determined the number of café-au-lait macules in two groups of people with NF1. We measured the gene expression of about 10,000 genes in the cultured white blood cells from one group of people. We then sequenced a group of genes whose expression level was increased in people with higher numbers of café-au-lait macules. In the first group, we found common variants in genes MSH6 and near DPH2 and ATP6V0B that were significantly associated with the number of café-au-lait macules. Some of these variants were close to significant in the second group of people. The two variants near DPH2 and ATP6V0B were very significant when analysed in both groups combined. Our work is among the first to identify genetic variants that influence the severity of NF1.
Vyšlo v časopise: Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004575 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004575
1. JettK, FriedmanJM (2010) Clinical and genetic aspects of neurofibromatosis 1. Genet Med 12 : 1–11.
2. ViskochilD (1999) In search of the Holy Grail: NF1 mutation analysis and genotype - phenotype correlation. Genet Med 1 : 245–247.
3. UpadhyayaM, HusonSM, DaviesM, ThomasN, ChuzhanovaN, et al. (2007) An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970–2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet 80 : 140–151.
4. DippleKM, McCabeER (2000) Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 71 : 43–50.
5. HoulstonRS, TomlinsonIP (1998) Modifier genes in humans: strategies for identification. Eur J Hum Genet 6 : 80–88.
6. CareyJC, ViskochilDH (1999) Neurofibromatosis type 1: A model condition for the study of the molecular basis of variable expressivity in human disorders. Am J Med Genet 89 : 7–13.
7. Amlin-Van SchaickJC, KimS, DiFabioC, LeeMH, BromanKW, et al. (2012) Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12. Neuro Oncol 14 : 160–174.
8. Amlin-Van SchaickJ, KimS, BromanKW, ReillyKM (2012) Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse Chr 5. Mamm Genome 23 : 277–285.
9. ReillyKM, BromanKW, BronsonRT, TsangS, LoiselDA, et al. (2006) An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model. Cancer Res 66 : 62–68.
10. ReillyKM, TuskanRG, ChristyE, LoiselDA, LedgerJ, et al. (2004) Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects. Proc Natl Acad Sci U S A 101 : 13008–13013.
11. EastonDF, PonderMA, HusonSM, PonderBA (1993) An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet 53 : 305–313.
12. SzudekJ, JoeH, FriedmanJM (2002) Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genet Epidemiol 23 : 150–164.
13. SabbaghA, PasmantE, LaurendeauI, ParfaitB, BarbarotS, et al. (2009) Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet 18 : 2768–2778.
14. BahuauM, PeletA, VidaudD, LamireauT, LeBailB, et al. (2001) GDNF as a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype. J Med Genet 38 : 638–643.
15. TitzeS, PetersH, WahrischS, HarderT, GuseK, et al. (2010) Differential MSH2 promoter methylation in blood cells of Neurofibromatosis type 1 (NF1) patients. Eur J Hum Genet 18 : 81–87.
16. PasmantE, VidaudD, HarrisonM, UpadhyayaM (2011) Different sized somatic NF1 locus rearrangements in neurofibromatosis 1-associated malignant peripheral nerve sheath tumors. J Neurooncol 102 : 341–346.
17. MussotterT, KluweL, HogelJ, NguyenR, CooperDN, et al. (2012) Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions. BMC Med Genet 13 : 98.
18. SchadtEE, MonksSA, DrakeTA, LusisAJ, CheN, et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422 : 297–302.
19. CheungVG, ConlinLK, WeberTM, ArcaroM, JenKY, et al. (2003) Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 33 : 422–425.
20. MorleyM, MolonyCM, WeberTM, DevlinJL, EwensKG, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430 : 743–747.
21. JansenRC, NapJP (2001) Genetical genomics: the added value from segregation. Trends Genet 17 : 388–391.
22. BystrykhL, WeersingE, DontjeB, SuttonS, PletcherMT, et al. (2005) Uncovering regulatory pathways that affect hematopoietic stem cell function using ‘genetical genomics’. Nat Genet 37 : 225–232.
23. CheslerEJ, LuL, ShouS, QuY, GuJ, et al. (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37 : 233–242.
24. HubnerN, WallaceCA, ZimdahlH, PetrettoE, SchulzH, et al. (2005) Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet 37 : 243–253.
25. EmilssonV, ThorleifssonG, ZhangB, LeonardsonAS, ZinkF, et al. (2008) Genetics of gene expression and its effect on disease. Nature 452 : 423–428.
26. LibioulleC, LouisE, HansoulS, SandorC, FarnirF, et al. (2007) Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet 3: e58.
27. DobrinR, ZhuJ, MolonyC, ArgmanC, ParrishML, et al. (2009) Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease. Genome Biol 10: R55.
28. McCarrollSA, HuettA, KuballaP, ChilewskiSD, LandryA, et al. (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 40 : 1107–1112.
29. MusunuruK, StrongA, Frank-KamenetskyM, LeeNE, AhfeldtT, et al. (2010) From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466 : 714–719.
30. CuiJ, StahlEA, SaevarsdottirS, MiceliC, DiogoD, et al. (2013) Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet 9: e1003394.
31. StrangerBE, RajT (2013) Genetics of human gene expression. Curr Opin Genet Dev 23 : 627–634.
32. MaertensO, De SchepperS, VandesompeleJ, BremsH, HeynsI, et al. (2007) Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet 81 : 243–251.
33. WhitesideD, McLeodR, GrahamG, SteckleyJL, BoothK, et al. (2002) A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res 62 : 359–362.
34. TrimbathJD, PetersenGM, ErdmanSH, FerreM, LuceMC, et al. (2001) Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC? Fam Cancer 1 : 101–105.
35. RicciardoneMD, OzcelikT, CevherB, OzdagH, TuncerM, et al. (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59 : 290–293.
36. Hindorff LA, MacArthur J, Wise A, Junkins HA, Hall PN, et al.. A catalog of published genome-wide association studies. Available: www.genome.gov/gwastudies. Accessed May 25, 2014.
37. BlattlerA, YaoL, WangY, YeZ, JinVX, et al. (2013) ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes. Epigenetics Chromatin 6 : 13.
38. CiprianoDJ, WangY, BondS, HintonA, JefferiesKC, et al. (2008) Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta 1777 : 599–604.
39. NelsonN, HarveyWR (1999) Vacuolar and plasma membrane proton-adenosinetriphosphatases. Physiol Rev 79 : 361–385.
40. NishiT, ForgacM (2002) The vacuolar (H+)-ATPases–nature's most versatile proton pumps. Nat Rev Mol Cell Biol 3 : 94–103.
41. ChiA, ValenciaJC, HuZZ, WatabeH, YamaguchiH, et al. (2006) Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes. J Proteome Res 5 : 3135–3144.
42. OrtonneJP, BrocardE, FloretD, PerrotH, ThivoletJ (1980) [Diagnostic value of cafe-au-lait spots (author's transl)]. Ann Dermatol Venereol 107 : 313–327.
43. WasmeierC, HumeAN, BolascoG, SeabraMC (2008) Melanosomes at a glance. J Cell Sci 121 : 3995–3999.
44. NavarroRE, Ramos-BalderasJL, GuerreroI, PelcastreV, MaldonadoE (2008) Pigment dilution mutants from fish models with connection to lysosome-related organelles and vesicular traffic genes. Zebrafish 5 : 309–318.
45. Ramos-BalderasJL, Carrillo-RosasS, GuzmanA, NavarroRE, MaldonadoE (2013) The zebrafish mutants for the V-ATPase subunits d, ac45, E, H and c and their variable pigment dilution phenotype. BMC Res Notes 6 : 39.
46. LiuS, WigginsJF, SreenathT, KulkarniAB, WardJM, et al. (2006) Dph3, a small protein required for diphthamide biosynthesis, is essential in mouse development. Mol Cell Biol 26 : 3835–3841.
47. GreganovaE, AltmannM, ButikoferP (2011) Unique modifications of translation elongation factors. FEBS J 278 : 2613–2624.
48. KongF, TongR, JiaL, WeiW, MiaoX, et al. (2011) OVCA1 inhibits the proliferation of epithelial ovarian cancer cells by decreasing cyclin D1 and increasing p16. Mol Cell Biochem 354 : 199–205.
49. WuY, BerendsMJ, MensinkRG, KempingaC, SijmonsRH, et al. (1999) Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet 65 : 1291–1298.
50. RaevaaraTE, GerdesAM, LonnqvistKE, Tybjaerg-HansenA, Abdel-RahmanWM, et al. (2004) HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. Genes Chromosomes Cancer 40 : 261–265.
51. MenkoFH, KaspersGL, MeijerGA, ClaesK, van HagenJM, et al. (2004) A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer. Fam Cancer 3 : 123–127.
52. OstergaardJR, SundeL, OkkelsH (2005) Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. Am J Med Genet A 139A: 96–105 discussion 196.
53. de VosM, HaywardB, BonthronDT, SheridanE (2005) Phenotype associated with recessively inherited mutations in DNA mismatch repair (MMR) genes. Biochem Soc Trans 33 : 718–720.
54. WimmerK, EtzlerJ (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124 : 105–122.
55. PetersA, BornH, EttingerR, LevonianP, JedeleKB (2009) Compound heterozygosity for MSH6 mutations in a pediatric lymphoma patient. J Pediatr Hematol Oncol 31 : 113–115.
56. WangQ, MontmainG, RuanoE, UpadhyayaM, DudleyS, et al. (2003) Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet 112 : 117–123.
57. FeitsmaH, KuiperRV, KorvingJ, NijmanIJ, CuppenE (2008) Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors. Cancer Res 68 : 5059–5066.
58. BoleyS, SloanJL, PemovA, StewartD (2009) A Quantitative Assessment of the Burden and Distribution of Lisch Nodules in Adults with Neurofibromatosis Type 1. Invest Ophthalmol Vis Sci 50 : 5035–5043.
59. RuggieriM, HusonSM (2001) The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 56 : 1433–1443.
60. ManolioTA, CollinsFS, CoxNJ, GoldsteinDB, HindorffLA, et al. (2009) Finding the missing heritability of complex diseases. Nature 461 : 747–753.
61. GeninE, FeingoldJ, Clerget-DarpouxF (2008) Identifying modifier genes of monogenic disease: strategies and difficulties. Hum Genet 124 : 357–368.
62. WalrathJC, FoxK, TrufferE, Gregory AlvordW, QuinonesOA, et al. (2009) Chr 19(A/J) modifies tumor resistance in a sex - and parent-of-origin-specific manner. Mamm Genome 20 : 214–223.
63. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 45 : 575–578.
64. GutmannDH, AylsworthA, CareyJC, KorfB, MarksJ, et al. (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278 : 51–57.
65. WerteleckiW, SuperneauDW, BlackburnWR, VarakisJN (1982) Neurofibromatosis, skin hemangiomas, and arterial disease. Birth Defects Orig Artic Ser 18 : 29–41.
66. WerteleckiW, SuperneauDW, ForehandLW, HoffCJ (1988) Angiomas and von Recklinghausen neurofibromatosis. Neurofibromatosis 1 : 137–145.
67. ClementiM, MilaniS, MammiI, BoniS, MonciottiC, et al. (1999) Neurofibromatosis type 1 growth charts. Am J Med Genet A 87 : 317–323.
68. BushbyKM, ColeT, MatthewsJN, GoodshipJA (1992) Centiles for adult head circumference. Arch Dis Child 67 : 1286–1287.
69. BenjaminiY, HochbergY (1995) Controlling the false discovery rate: A new and powerful approach to multiple testing. J Roy Stat Soc Series B 57 : 1289–1300.
70. O'ConnellJR, WeeksDE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63 : 259–266.
71. WiggintonJE, AbecasisGR (2005) PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 21 : 3445–3447.
72. SungH, KimY, CaiJ, CroppCD, SimpsonCL, et al. (2011) Comparison of results from tests of association in unrelated individuals with uncollapsed and collapsed sequence variants using tiled regression. BMC Proc 5 Suppl 9: S15.
73. LiptakT (1958) On the combination of independent tests. Magyar Tud Akad Mat Kutato Int Kozl 3 : 171–197.
74. RosenbloomKR, SloanCA, MalladiVS, DreszerTR, LearnedK, et al. (2013) ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res 41: D56–63.
75. MeyerLR, ZweigAS, HinrichsAS, KarolchikD, KuhnRM, et al. (2013) The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res 41: D64–69.
76. ChadwickLH (2012) The NIH Roadmap Epigenomics Program data resource. Epigenomics 4 : 317–324.
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