DNA repair/replication transcripts are down regulated in patients with Fragile X Syndrome

BMC Research Notes

Emmanuel Peprah²  Patricio Barros-Núñez¹  Mónica A Rosales-Reynoso¹  Huichun Xu² 

[1] Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguo Social, Sierra Mojada 800. Col. Independencia, Guadalajara, Jalisco, 44340, Mexico;Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Dr. MSC 5635, Bethesda, MD 20892, USA

关键词: DNA repair/replication proteins;    FMR1;    Haploinsufficiency;   

Others  :  1143298
DOI  :  10.1186/1756-0500-6-90

 received in 2012-07-30, accepted in 2013-02-22,  发布年份 2013

【 摘 要 】

Background

Fragile X Syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene, with disease classification based on the number of CGG repeats. The mechanisms of repeat expansion are dependent on the presence of cis elements and the absence of trans factors both of which are not mutually exclusive and contribute to repeat instability. Expansions associated with trans factors are due to the haploinsuffient or reduced expression of several DNA repair/metabolizing proteins. The reduction of expression in trans factors has been primarily conducted in animal models without substantial examination of many of these expansion mechanisms and trans factors in humans.

Results

To understand the trans factors and pathways associated with trinucleotide repeat expansion we have analyzed two microarray datasets which characterized the transcript expression in patients with FXS and in controls.

Conclusion

We observed significant down regulation of DNA damage/repair pathway transcripts. This observation was consistent in both datasets, which used different populations. Within these datasets, several transcripts overlapped in the direction of association and fold change. Further characterization of these genes will be critical to understand their role in trinucleotide repeat instability in FXS.

【 授权许可】

   
2013 Xu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Crawford D, Acuna J, Sherman S: FMR1 and the Fragile X syndrome: human genome epidemiology review. Genet Med 2001, 3(5):359-371.
• [2]Garber K, Smith K, Reines D, Warren S: Transcription, translation and Fragile X Syndrome. Curr Opin Genet Dev 2006, 16:270-275.
• [3]Coffee B, Keith K, Albizua I, Malone T, Mowery J, Sherman S, Warren S: Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet 2009, 85:503-514.
• [4]Fengler S, Fuchs S, Konig R, Arnemann J: Mosaicism for FMR1 and FMR2 deletion: a new case. J Med Genet 2002, 39:200-201.
• [5]Han X-D, Powell B, Phalin J, Chehab F: Mosaicism for a Full mutation, Premutation and Deletion of the CGG Repeats results in 22% FMRP and elevated FMR1 mRNA levels in a high functioning Fragile X male. Am J Med Genet A 2006, 140A:1463-1471.
• [6]Fu Y, Kuhl D, Pizzuti A, Pieretti M, Sutcliffe J, Richards S, Verkerk A, Holden J, Fenwick R, Warren S: Variation of the CGG repeat at the Fragile X site results in gene instability: resolution of the Sherman paradox. Cell 1991, 67:1047-1058.
• [7]Verkerk A, Pieretti M, Sutcliffe J, Fu Y, Pizzuti A, Reiner O, Richards S, Victoria M, Zhang F: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in Fragile X syndrome. Cell 1991, 65:905-914.
• [8]Sutcliffe J, Nelson D, Zhang F, Pieretti M, Caskey T, Saxe D, Warren S: DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1992, 1:397-400.
• [9]Yrigollen CM, Durbin-Johnson B, Gane L, Nelson DL, Hagerman R, Hagerman PJ, Tassone F: AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet Med 2012, 14(8):729-736.
• [10]Zeesman S, Zwaigenbaum L, Whelan D, Hagerman R, Tassone F, Taylor S: Parental Transmission of Fragile X Syndrome. Am J Med Genet A 2004, 129A:184-189.
• [11]Foulkes W: Inherited susceptibility to common cancers. N Engl J Med 2008, 359:2143-2153.
• [12]McMurray CT: Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 2010, 11(11):786-799.
• [13]Entezam A, Usdin K: ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice. Nucleic Acids Res 2009, 37(19):6371-6377.
• [14]Entezam A, Usdin K: ATR protects the genome against CGG. CCG-repeat expansion in Fragile X premutation mice. Nucleic Acids Res 2008, 36(3):1050-1056.
• [15]Rosales-Reynoso MA, Ochoa-Hernandez AB, Aguilar-Lemarroy A, Jave-Suarez LF, Troyo-Sanroman R, Barros-Nunez P: Gene expression profiling identifies WNT7A as a possible candidate gene for decreased cancer risk in fragile X syndrome patients. Arch Med Res 2010, 41(2):110-118.
• [16]Nishimura Y, Martin CL, Lopez AV, Spence SJ, Alvarez-Retuerto AI, Sigman M, Steindler C, Pellegrini S, Schanen NC, Warren ST: Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 2007, 16(14):1682-1698.
• [17]Urbach A, Bar-Nur O, Daley GQ, Benvenisty N: Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 2010, 6(5):407-411.
• [18]Bittel DC, Kibiryeva N, Butler MG: Whole genome microarray analysis of gene expression in subjects with fragile X syndrome. Genet Med 2007, 9(7):464-472.
• [19]Nolin SL, Lewis FA 3rd, Ye LL, Houck GE Jr, Glicksman AE, Limprasert P, Li SY, Zhong N, Ashley AE, Feingold E: Familial transmission of the FMR1 CGG repeat. Am J Hum Genet 1996, 59(6):1252-1261.