Abstract
Fragile X syndrome is caused by dynamic mutation of FMR1 gene CpG island CGG repeats. The underlying mutational mechanism is not fully understood. Different microsatellite markers and SNP have previously been reported as markers associated with FMR1 CGG repeat instability. The aim of the present study was to identify specific haplotypes among Latvian FXS patients and the control group with respect to allelic stability. Eleven male FXS patients and 122 control male patients participated in the study. In total, 27 different DXS548-FRAXAC1-ATL1-FRAXAC2 haplotypes were found. The prevalent haplotype in the control group was 7-4-A-5+ (rel. frequency 0.327). The prevalent haplotype associated with the FXS group was 2-2-G-4 (rel. frequency 0.818; p < 0.0001). Grey zone alleles with a long uninterrupted CGG tract at the 3’ end were significantly associated with the 2-2-G-4 haplotype (p = 0.0022). Our findings suggest that, for the Latvian population, the haplotype 2-2-G-4 is a marker of CGG tract instability. We conclude that a founder effect could not be an explanation for our findings on the basis of heterogeneity exhibited by the Latvian population and lack of studies throughout this geographical region. This data may provide evidence of different mutational pathways of expansion in the Baltic States region.
[1] Crawford, D. C., Acuna, J. M. and Sherman, S. L. FMR1 and the fragile X syndrome: Human genome epidemiology review. Genetics in Medicine, 2001, 3(5), 359–371 http://dx.doi.org/10.1097/00125817-200109000-0000610.1097/00125817-200109000-00006Search in Google Scholar
[2] Oberle I., Rousseau F., Heitz D., Devys D., Hanauer A., Boue J., et al., Instability of a 550-Base Pair DNA Segment and Abnormal Methylation in Fragile X Syndrome. Science., 1991, 252, 1097–1102 http://dx.doi.org/10.1126/science.252.5009.109710.1126/science.252.5009.1097Search in Google Scholar
[3] Poustka A., Dietrich A., Langenstein G., Toniolo D., Warren S. T., and Lehrach H., Physical map of human Xq27-qter: Localizing the region of the fragile X mutation. Proc. Natl. Acad. Sci. USA, 1991, 88, 8302–8306 http://dx.doi.org/10.1073/pnas.88.19.830210.1073/pnas.88.19.8302Search in Google Scholar
[4] Rousseau F., Heitz D., Oberle I., and Mandel J-L., Selection in blood cells from female carriers of the fragile X syndrome: inverse correlation between age and proportion of active X chromosomes carrying the full mutation. J. Med. Genet., 1991, 28, 830–836 http://dx.doi.org/10.1136/jmg.28.12.83010.1136/jmg.28.12.830Search in Google Scholar
[5] Eichler E. E., Macpherson J. N., Murray A., Jacobs P. A., Chakravarti A., and Nelson D. L., Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome. Hum. Mol. Genet., 1996, 5, 319–330 http://dx.doi.org/10.1093/hmg/5.3.31910.1093/hmg/5.3.319Search in Google Scholar
[6] Fu Y. H., Kuhl D. P. A., Pizzuti A., Pieretti M., Sutcliffe J. S., Richards S., et al., Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell, 1991, 67, 1047–1058 http://dx.doi.org/10.1016/0092-8674(91)90283-510.1016/0092-8674(91)90283-5Search in Google Scholar
[7] de Vries B. B. A., Halley D. J. J., Oostra B. A., and Niermeijer M. F., The fragile X syndrome. J.Med. Genet., 1998, 35, 579–589 http://dx.doi.org/10.1136/jmg.35.7.57910.1136/jmg.35.7.579Search in Google Scholar PubMed PubMed Central
[8] Moutou C., Vincent M. C., Biancalana V., and Mandel J-L., Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic. 1997, Hum. Mol. Genet., 3, 971–979 http://dx.doi.org/10.1093/hmg/6.7.97110.1093/hmg/6.7.971Search in Google Scholar PubMed
[9] Rife M., Badenas C., Quinto Ll., Puigoriol E., Tazon B., Rodriguez-Revenga L., et al., Analysis of CGG variation through 642 meioses in Fragile X families. Mol. Hum. Reprod., 2004, 10, 773–779 http://dx.doi.org/10.1093/molehr/gah10210.1093/molehr/gah102Search in Google Scholar PubMed
[10] Sherman S., Plecher B. A., and Driscoll D. A., Fragile X syndrome: Diagnostic and carrier testing. Genetics in Medicine, 2005, 7, 584–587 http://dx.doi.org/10.1097/01.GIM.0000182468.22666.dd10.1097/01.GIM.0000182468.22666.ddSearch in Google Scholar PubMed PubMed Central
[11] Dombrowski C., Levesque S., Morel M. L., Rouillard P., Morgan K., and Rousseau F., Premutation and intermediate-size FMR1 alleles in 10 572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum. Mol. Genet., 2002, 11, 371–378 http://dx.doi.org/10.1093/hmg/11.4.37110.1093/hmg/11.4.371Search in Google Scholar PubMed
[12] Gunter C., Paradee W., Crawford D. C., Meadows K. A., Newman J., Kunst C. B., et al., Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1. Hum. Mol. Genet., 1998, 7, 1935–1946 http://dx.doi.org/10.1093/hmg/7.12.193510.1093/hmg/7.12.1935Search in Google Scholar PubMed
[13] Kunst C. B., Zerylnick C., Karickhoff L., Eichler E., Bullard J., Chalifoux M., et al., FMR1 in Global Populations. Am. J. Hum. Genet., 1996, 58, 513–522 Search in Google Scholar
[14] Macpherson J. N., Bullman H., Youings S. A., and Jacobs P. A., Insert size and flanking haplotype in fragile X and normal population: possible multiple origins for the fragile X mutations. Hum. Mol. Genet., 1994, 3, 399–405 http://dx.doi.org/10.1093/hmg/3.3.39910.1093/hmg/3.3.399Search in Google Scholar PubMed
[15] Murray A., Macpherson J. N., Pound M. C., Sharrock A., Youings S. A., Dennis N. R., et al., The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission. Hum. Mol. Genet., 1997, 6, 173–184 http://dx.doi.org/10.1093/hmg/6.2.17310.1093/hmg/6.2.173Search in Google Scholar PubMed
[16] Oudet C., Mornet E., Serre J. L., Thomas F., Lentes-Zengerling S., Kretz C., et al., Linkage disequilibrium between the fragile X mutation two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes. Am. J. Hum. Genet., 1993, 52, 297–304 Search in Google Scholar
[17] Richards R. I., Holman K., Kozman H., Kremer E., Pritchard M., Yu s., et al., Fragile X syndrome: genetic localisation by linkige mapping of two microsatellite repeats FRAXAC1 and FRAXAC2 which immediately flank the fragile site. J. Hum. Genet., 1991, 28, 818–823 10.1136/jmg.28.12.818Search in Google Scholar PubMed PubMed Central
[18] Chong S. S., Eichler E. E., Nelson D. L., and Hughes M. R., Robust amplification and ethidium — visible detection of the fragile X syndrome CGG repeat using Pfu polymerase. Am. J. Med. Genet., 1994, 51, 522–526 http://dx.doi.org/10.1002/ajmg.132051044710.1002/ajmg.1320510447Search in Google Scholar PubMed
[19] Crawford D. C., Shwartz C. E., Meadows K. L., Newman J. L., Taft L. F., Gunter C., et al., Survey of the Fragile X Syndrome CGG Repeat and the Short-Tandem-Repeat and Single-Nucleotid-Polymorphism Haplotypes in an African American Population. Am. J. Med. Genet., 2000, 66, 480–493 10.1086/302762Search in Google Scholar PubMed PubMed Central
[20] Chiurazzi P., DNA panel to interlaboratory standardization of haplotype studies on the fragile X syndrome and proposal for a new allele nomenclature. Am. J. Med. Genet., 1999, 83, 347–349 http://dx.doi.org/10.1002/(SICI)1096-8628(19990402)83:4<347::AID-AJMG25>3.0.CO;2-#Search in Google Scholar
[21] Excoffier L. and Lischer H.E. L., Arlequin suite ver. 3.5: A new series of programs to perform population genetics analyses under Linux and Windows. Molecular Ecology Resources., 2010, 10, 564–567 http://dx.doi.org/10.1111/j.1755-0998.2010.02847.x10.1111/j.1755-0998.2010.02847.xSearch in Google Scholar PubMed
[22] Arrieta I., Penagarikano O., Telez M., Ortega B., Flores P., Criado B., et al., The FMR1 CGG repeat and linked microsatellite markers in two Basque valleys, Heredity, 2003, 90, 206–211 http://dx.doi.org/10.1038/sj.hdy.680021810.1038/sj.hdy.6800218Search in Google Scholar PubMed
[23] Curlis Y., Zhang C., Holden J. J. A., Kirkby K., Loesch D., and Mitchell R. J., Haplotype study of intermediate-length alleles at the fragile X (FMR1) gene: ATL1, FMRb, and microsatellite haplotypes differ from those found in common-size FMR1 alleles. Hum. Biol., 2005, 77, 137–151 http://dx.doi.org/10.1353/hub.2005.002910.1353/hub.2005.0029Search in Google Scholar PubMed
[24] Zhou Y., Tang K., Law H. Y., Ng I. S. L., Lee C. G. L., and Chong S. S., FMR1 CGG repeat patterns and flanking haplotypes in three Asian populations and their relationship with repeat instability. Ann. Hum. Genet., 2006, 70, 784–796 http://dx.doi.org/10.1111/j.1469-1809.2006.00265.x10.1111/j.1469-1809.2006.00265.xSearch in Google Scholar
[25] Dokic H., Barišic I., Čulic V., Lozic B., and Hecimovic S., Haplotype and AGG interspersion analysis of FMR1 alleles in a Croatian population: no founder effect detected in patients with fragile X syndrome. Hum. Biol., 2008, 80, 581–587 http://dx.doi.org/10.3378/1534-6617-80.5.58110.3378/1534-6617-80.5.581Search in Google Scholar
[26] Malmgren H., Gustavson K. H., Oudet C., et al., Strong founder effect for the fragile X syndrome in Sweden. Eur. J. Hum. Genet., 1994, 2, 103–109 10.1159/000472350Search in Google Scholar
[27] Peixoto A., dos Santos M. R., Seruca R., Amorim A., and Castedo S., Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype. Eur. J. Hum. Genet., 1998, 6, 518–522. http://dx.doi.org/10.1038/sj.ejhg.520020410.1038/sj.ejhg.5200204Search in Google Scholar
[28] Pekarik V., Blazkova M., and Kozak L., Haplotype analysis of the fragile X syndrome gene FMR1 in the Czech Republic. Am. J. Med. Genet., 1999, 84, 214–21 http://dx.doi.org/10.1002/(SICI)1096-8628(19990528)84:3<214::AID-AJMG9>3.0.CO;2-A10.1002/(SICI)1096-8628(19990528)84:3<214::AID-AJMG9>3.0.CO;2-ASearch in Google Scholar
[29] Rajkiewicz M., Molecular analysis of the FMR1 gene and searching for the premutations in the large group of Polish ataxia patients and group of women with premature ovarian failure. PhD thesis, Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland, 2008 Search in Google Scholar
[30] Haataja R., Vaisanen M. L., Li M., Muyao L., Ryynanen M., and Leisti J., The fragile X syndrome in Finland: demonstration of a founder effect by analysis of microsatellite haplotypes. Hum. Genet., 1994, 94, 479–483 http://dx.doi.org/10.1007/BF0021101110.1007/BF00211011Search in Google Scholar
[31] Drozd O. V., Strelnikov V. V., Babenko O. V., Zemlyakova V.V., Nemtsova M. V., and Zaletaev D. V., Allelic polymorphism of the five X-linked (CA)n dinucleotide repeats in Russia. Genetica., 2003, 39, 433–438 Search in Google Scholar
[32] Larsen L. A., Vuust J., Nystad M., Evseeva I., Van Ghelue M., and Tranebjaerg L., Analysis of FMR1 (CGG)n alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia. Eur. J. Hum. Genet., 2001, 9, 724–727 http://dx.doi.org/10.1038/sj.ejhg.520069710.1038/sj.ejhg.5200697Search in Google Scholar
© 2011 Versita Warsaw
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
