Biopolym. Cell. 1998; 14(1):5-11.
http://dx.doi.org/10.7124/bc.0004B1
Reviews
Molecular and genetic aspects of fragile X syndrome (Martin-Bell)
1Malyarchuk S. C.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

Fragile X syndrome (Martin-Bell) is a common cause of mental retardation that is inherited as an X-linked dominant disorder with reduced penetrance. The incidence of fragile X syndrome is estimated to be approximately one pur 1500 males and one per 2500 females. This review represents the modern data about FMRI gene structure, dynamic mutations caused by expansion of intragenic CGG-trinucleolide repeals as well as other types of mutations at that gene.
Full text: (PDF, in Russian)

References

[1] Richards RI, Sutherland GR. Dynamic mutations: a new class of mutations causing human disease. Cell. 1992;70(5):709-12.
[2] Willems PJ. Dynamic mutations hit double figures. Nat Genet. 1994;8(3):213-5.
[3] McKusick VA, Francomono CA, Antonarakis SE. Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes.-Baltimore: The Johns Hopkins Univ. press. 1994;2452-61.
[4] Webb TP, Bundey SE, Thake AI, Todd J. Population incidence and segregation ratios in the Martin-Bell syndrome. Am J Med Genet. 1986;23(1-2):573-80.
[5] Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al. 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(5):905-14.
[6] Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67(6):1047-58.
[7] Snow K, Doud LK, Hagerman R, Pergolizzi RG, Erster SH, Thibodeau SN. Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population. Am J Hum Genet. 1993;53(6):1217-28.
[8] Rousseau F, Heitz D, Biancalana V, Blumenfeld S, Kretz C, Bou? J, Tommerup N, Van Der Hagen C, DeLozier-Blanchet C, Croquette MF, et al. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med. 1991;325(24):1673-81.
[9] Richards RI, Sutherland GR. Heritable unstable DNA sequences. Nat Genet. 1992;1(1):7-9.
[10] Warren ST, Nelson DL. Advances in molecular analysis of fragile X syndrome. JAMA. 1994;271(7):536-42.
[11] Heitz D, Devys D, Imbert G, Kretz C, Mandel JL. Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation. J Med Genet. 1992;29(11):794-801.
[12] Fisch GS, Snow K, Thibodeau SN, Chalifaux M, Holden JJ, Nelson DL, Howard-Peebles PN, Maddalena A. The fragile X premutation in carriers and its effect on mutation size in offspring. Am J Hum Genet. 1995;56(5):1147-55.
[13] Reiss AL, Kazazian HH Jr, Krebs CM, McAughan A, Boehm CD, Abrams MT, Nelson DL. Frequency and stability of the fragile X premutation. Hum Mol Genet. 1994;3(3):393-8.
[14] Nelson DL. Characterization of the FRAX(A) locus in man. Am J Hum Genet. 1992; 51: A186.
[15] Reyniers E, Vits L, De Boulle K, Van Roy B, Van Velzen D, de Graaff E, Verkerk AJ, Jorens HZ, Darby JK, Oostra B, et al. The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. Nat Genet. 1993;4(2):143-6.
[16] Willems PJ, Van Roy B, De Boulle K, Vits L, Reyniers E, Beck O, Dumon JE, Verkerk A, Oostra B. Segregation of the fragile X mutation from an affected male to his normal daughter. Hum Mol Genet. 1992;1(7):511-5.
[17] Mulley JC, Yu S, Gedeon AK, Donnelly A, Turner G, Loesch D, Chapman CJ, Gardner RJ, Richards RI, Sutherland GR. Experience with direct molecular diagnosis of fragile X. J Med Genet. 1992;29(6):368-74.
[18] W?hrle D, Hennig I, Vogel W, Steinbach P. Mitotic stability of fragile X mutations in differentiated cells indicates early post-conceptional trinucleotide repeat expansion. Nat Genet. 1993;4(2):140-2.
[19] W?hrle D, Hirst MC, Kennerknecht I, Davies KE, Steinbach P. Genotype mosaicism in fragile X fetal tissues. Hum Genet. 1992;89(1):114-6.
[20] Devys D, Biancalana V, Rousseau F, Bou? J, Mandel JL, Oberl? I. Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am J Med Genet. 1992 Apr 15-May 1;43(1-2):208-16.
[21] Richards RI, Sutherland GR. Simple repeat DNA is not replicated simply. Nat Genet. 1994;6(2):114–6.
[22] Parsons R, Li GM, Longley MJ, Fang WH, Papadopoulos N, Jen J, de la Chapelle A, Kinzler KW, Vogelstein B, Modrich P. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. 1993;75(6):1227-36.
[23] Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994;8(1):88-94.
[24] Alexiou M, Leese HJ. Purine utilisation, de novo synthesis and degradation in mouse preimplantation embryos. Development. 1992;114(1):185-92.
[25] Nethanel T, Zlotkin T, Kaufmann G. Assembly of simian virus 40 Okazaki pieces from DNA primers is reversibly arrested by ATP depletion. J Virol. 1992;66(11):6634-40.
[26] Macpherson JN, Bullman H, Youings SA, Jacobs PA. Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation. Hum Mol Genet. 1994;3(3):399-405.
[27] Chung MY, Ranum LP, Duvick LA, Servadio A, Zoghbi HY, Orr HT. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet. 1993;5(3):254-8.
[28] Zhong N, Yang W, Dobkin C, Brown WT. Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Hum Genet. 1995;57(2):351-61.
[29] Weber JL. Informativeness of human (dC-dA)n.(dG-dT)n polymorphisms. Genomics. 1990;7(4):524-30.
[30] Kunst CB, Warren ST. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell. 1994;77(6):853-61.
[31] Armour JA, Harris PC, Jeffreys AJ. Allelic diversity at minisatellite MS205 (D16S309): evidence for polarized variability. Hum Mol Genet. 1993;2(8):1137-45.
[32] Jeffreys AJ, Tamaki K, MacLeod A, Monckton DG, Neil DL, Armour JA. Complex gene conversion events in germline mutation at human minisatellites. Nat Genet. 1994;6(2):136-45.
[33] Knight SJ, Flannery AV, Hirst MC, Campbell L, Christodoulou Z, Phelps SR, Pointon J, Middleton-Price HR, Barnicoat A, Pembrey ME, et al. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell. 1993;74(1):127-34.
[34] La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77-9.
[35] Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994;6(1):9-13.
[36] Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992;68(4):799-808.
[37] A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993;72(6):971-83.
[38] Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet. 1994;6(1):14-8.
[39] Vits L, De Boulle K, Reyniers E, Handig I, Darby JK, Oostra B, Willems PJ. Apparent regression of the CGG repeat in FMR1 to an allele of normal size. Hum Genet. 1994;94(5):523-6.
[40] van den Ouweland AM, de Vries BB, Bakker PL, Deelen WH, de Graaff E, van Hemel JO, Oostra BA, Niermeijer MF, Halley DJ. DNA diagnosis of the fragile X syndrome in a series of 236 mentally retarded subjects and evidence for a reversal of mutation in the FMR-1 gene. Am J Med Genet. 1994;51(4):482-5.
[41] van den Ouweland AM, Deelen WH, Kunst CB, Uzielli ML, Nelson DL, Warren ST, Oostra BA, Halley DJ. Loss of mutation at the FMR1 locus through multiple exchanges between maternal X chromosomes. Hum Mol Genet. 1994;3(10):1823-7.
[42] Brunner HG, Jansen G, Nillesen W, Nelen MR, de Die CE, H?weler CJ, van Oost BA, Wieringa B, Ropers HH, Smeets HJ. Brief report: reverse mutation in myotonic dystrophy. N Engl J Med. 1993;328(7):476-80.
[43] Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993;4(4):398-403.
[44] Knight SJ, Voelckel MA, Hirst MC, Flannery AV, Moncla A, Davies KE. Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap. Am J Hum Genet. 1994;55(1):81-6.
[45] Amato AA, Prior TW, Barohn RJ, Snyder P, Papp A, Mendell JR. Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. 1993;43(4):791-4.
[46] Gaillard C, Strauss F. Association of poly(CA).poly(TG) DNA fragments into four-stranded complexes bound by HMG1 and 2. Science. 1994;264(5157):433-6.
[47] Gedeon AK, Baker E, Robinson H, Partington MW, Gross B, Manca A, Korn B, Poustka A, Yu S, Sutherland GR, et al. Fragile X syndrome without CCG amplification has an FMR1 deletion. Nat Genet. 1992;1(5):341-4.
[48] W?hrle D, Kotzot D, Hirst MC, Manca A, Korn B, Schmidt A, Barbi G, Rott HD, Poustka A, Davies KE, et al. A microdeletion of less than 250 kb, including the proximal part of the FMR-I gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome. Am J Hum Genet. 1992;51(2):299-306.
[49] Trottier Y, Imbert G, Poustka A, Fryns JP, Mandel JL. Male with typical fragile X phenotype is deleted for part of the FMR1 gene and for about 100 kb of upstream region. Am J Med Genet. 1994;51(4):454-7.
[50] Hirst M, Grewal P, Flannery A, Slatter R, Maher E, Barton D, Fryns JP, Davies K. Two new cases of FMR1 deletion associated with mental impairment. Am J Hum Genet. 1995;56(1):67-74.
[51] Meijer H, de Graaff E, Merckx DM, Jongbloed RJ, de Die-Smulders CE, Engelen JJ, Fryns JP, Curfs PM, Oostra BA. A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum Mol Genet. 1994;3(4):615-20.
[52] De Boulle K, Verkerk AJ, Reyniers E, Vits L, Hendrickx J, Van Roy B, Van den Bos F, de Graaff E, Oostra BA, Willems PJ. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet. 1993;3(1):31-5.
[53] Mila M, Castellm-Bel S, Barcelo A et al. Mutations in the CpG island of the FMRI gene: are they responsible for the Fragile X Syndrome. Am J Hum Genet. 1995. 57, N 4: A220.