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2011 | 6 | 6 | 750-757
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FMR1 Linked haplotype analysis in a mentally retarded male population

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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.
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Opis fizyczny
  • Medical Genetic Clinic, University Children’s Hospital, Juglas Street 20, LV-1079, Riga, Latvia
  • [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[Crossref]
  • [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
  • [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[Crossref]
  • [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[Crossref]
  • [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[Crossref]
  • [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[Crossref]
  • [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[Crossref]
  • [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[Crossref]
  • [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
  • [10] Sherman S., Plecher B. A., and Driscoll D. A., Fragile X syndrome: Diagnostic and carrier testing. Genetics in Medicine, 2005, 7, 584–587[Crossref]
  • [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[Crossref]
  • [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[Crossref]
  • [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
  • [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[Crossref]
  • [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[Crossref]
  • [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
  • [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
  • [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[Crossref]
  • [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
  • [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<347::AID-AJMG25>3.0.CO;2-#[Crossref]
  • [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[WoS][Crossref]
  • [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[Crossref]
  • [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
  • [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[Crossref]
  • [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[Crossref]
  • [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
  • [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.[Crossref]
  • [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<214::AID-AJMG9>3.0.CO;2-A[Crossref]
  • [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
  • [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[Crossref]
  • [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
  • [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
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