Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1994 Jul;55(1):81–86.

Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap.

S J Knight 1, M A Voelckel 1, M C Hirst 1, A V Flannery 1, A Moncla 1, K E Davies 1
PMCID: PMC1918210  PMID: 8023854

Abstract

We have recently shown that the expression of the FRAXE fragile site in Xq28 is associated with the expansion of a GCC trinucleotide repeat. In the families studied, FRAXE expression is also associated with mild mental handicap. Here we present data on families that previously had been diagnosed as having the fragile X syndrome but that later were found to be negative for trinucleotide repeat expansion at the FRAXA locus. In these families we demonstrate the presence of a GCC trinucleotide repeat expansion at the FRAXE locus. Studies of the FRAXE locus of normal individuals show that they have 6-25 copies of the repeat, whereas affected individuals have > 200 copies. As in the fragile X syndrome, the amplified CpG residues are methylated in affected males.

Full text

PDF
81

Images in this article

84Figure 2
on p.84
84Figure 3
on p.84
85Figure 4
on p.85

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Clarke A., Bradley D., Gillespie K., Rees D., Holland A., Thomas N. S. Fragile X mental retardation and the iduronate sulphatase locus: testing Laird's model of fra(X) inheritance. 1992 Apr 15-May 1Am J Med Genet. 43(1-2):299–306. doi: 10.1002/ajmg.1320430146. [DOI] [PubMed] [Google Scholar]
  2. De Boulle K., Verkerk A. J., Reyniers E., Vits L., Hendrickx J., Van Roy B., Van den Bos F., de Graaff E., Oostra B. A., Willems P. J. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet. 1993 Jan;3(1):31–35. doi: 10.1038/ng0193-31. [DOI] [PubMed] [Google Scholar]
  3. Dennis N. R., Curtis G., Macpherson J. N., Jacobs P. A. Two families with Xq27.3 fragility, no detectable insert in the FMR-1 gene, mild mental impairment, and absence of the Martin-Bell phenotype. 1992 Apr 15-May 1Am J Med Genet. 43(1-2):232–236. doi: 10.1002/ajmg.1320430137. [DOI] [PubMed] [Google Scholar]
  4. Flynn G. A., Hirst M. C., Knight S. J., Macpherson J. N., Barber J. C., Flannery A. V., Davies K. E., Buckle V. J. Identification of the FRAXE fragile site in two families ascertained for X linked mental retardation. J Med Genet. 1993 Feb;30(2):97–100. doi: 10.1136/jmg.30.2.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gedeon A. K., Baker E., Robinson H., Partington M. W., Gross B., Manca A., Korn B., Poustka A., Yu S., Sutherland G. R. Fragile X syndrome without CCG amplification has an FMR1 deletion. Nat Genet. 1992 Aug;1(5):341–344. doi: 10.1038/ng0892-341. [DOI] [PubMed] [Google Scholar]
  6. Hansen R. S., Canfield T. K., Lamb M. M., Gartler S. M., Laird C. D. Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell. 1993 Jul 2;73(7):1403–1409. doi: 10.1016/0092-8674(93)90365-w. [DOI] [PubMed] [Google Scholar]
  7. Hansen R. S., Gartler S. M., Scott C. R., Chen S. H., Laird C. D. Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum Mol Genet. 1992 Nov;1(8):571–578. doi: 10.1093/hmg/1.8.571. [DOI] [PubMed] [Google Scholar]
  8. Hirst M. C., Barnicoat A., Flynn G., Wang Q., Daker M., Buckle V. J., Davies K. E., Bobrow M. The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE. Hum Mol Genet. 1993 Feb;2(2):197–200. doi: 10.1093/hmg/2.2.197. [DOI] [PubMed] [Google Scholar]
  9. Knight S. J., Flannery A. V., Hirst M. C., Campbell L., Christodoulou Z., Phelps S. R., Pointon J., Middleton-Price H. R., Barnicoat A., Pembrey M. E. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell. 1993 Jul 16;74(1):127–134. doi: 10.1016/0092-8674(93)90300-f. [DOI] [PubMed] [Google Scholar]
  10. Nakahori Y., Knight S. J., Holland J., Schwartz C., Roche A., Tarleton J., Wong S., Flint T. J., Froster-Iskenius U., Bentley D. Molecular heterogeneity of the fragile X syndrome. Nucleic Acids Res. 1991 Aug 25;19(16):4355–4359. doi: 10.1093/nar/19.16.4355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Oberlé I., Rousseau F., Heitz D., Kretz C., Devys D., Hanauer A., Boué J., Bertheas M. F., Mandel J. L. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991 May 24;252(5009):1097–1102. doi: 10.1126/science.252.5009.1097. [DOI] [PubMed] [Google Scholar]
  12. Reyniers E., Vits L., De Boulle K., Van Roy B., Van Velzen D., de Graaff E., Verkerk A. J., Jorens H. Z., Darby J. K., Oostra B. The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. Nat Genet. 1993 Jun;4(2):143–146. doi: 10.1038/ng0693-143. [DOI] [PubMed] [Google Scholar]
  13. Sutcliffe J. S., Nelson D. L., Zhang F., Pieretti M., Caskey C. T., Saxe D., Warren S. T. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet. 1992 Sep;1(6):397–400. doi: 10.1093/hmg/1.6.397. [DOI] [PubMed] [Google Scholar]
  14. Sutherland G. R., Baker E. Characterisation of a new rare fragile site easily confused with the fragile X. Hum Mol Genet. 1992 May;1(2):111–113. doi: 10.1093/hmg/1.2.111. [DOI] [PubMed] [Google Scholar]
  15. Verkerk A. J., Pieretti M., Sutcliffe J. S., Fu Y. H., Kuhl D. P., Pizzuti A., Reiner O., Richards S., Victoria M. F., Zhang F. P. 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 May 31;65(5):905–914. doi: 10.1016/0092-8674(91)90397-h. [DOI] [PubMed] [Google Scholar]
  16. Voelckel M. A., Philip N., Piquet C., Pellissier M. C., Oberlé I., Birg F., Mattei M. G., Mattei J. F. Study of a family with a fragile site of the X chromosome at Xq27-28 without mental retardation. Hum Genet. 1989 Mar;81(4):353–357. doi: 10.1007/BF00283690. [DOI] [PubMed] [Google Scholar]
  17. Wöhrle D., Kotzot D., Hirst M. C., Manca A., Korn B., Schmidt A., Barbi G., Rott H. D., Poustka A., Davies K. E. 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 Aug;51(2):299–306. [PMC free article] [PubMed] [Google Scholar]
  18. Yu S., Pritchard M., Kremer E., Lynch M., Nancarrow J., Baker E., Holman K., Mulley J. C., Warren S. T., Schlessinger D. Fragile X genotype characterized by an unstable region of DNA. Science. 1991 May 24;252(5009):1179–1181. doi: 10.1126/science.252.5009.1179. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES