Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island

Abstract

Five folate-sensitive fragile sites have been identi-fied at the molecular level to date1–8. Each is characterized by an expanded and methylated trinucleotide repeat of CGG (CCG). Of the three X chromosome sites, FRAXA, FRAXE and FRAXF, the former two are associated with mental retar-dation in their expanded forms. FRAXA expansion results in fragile X syndrome due to down regula-tion of expression of the FMR1 gene, which carries the hypermutable CGG repeat in the 5′ untranslated portion of its first exon9,10. Mild mental retardation without ponsistent physical findings has been found associated with expanded CCG repeats at FRAXE11–13. We have identified a large gene (FMR2) transcribed distally from the CpG island at FRAXE, and down-regulated by repeat expansion and methylation. The gene is novel, expressed in adult brain and placenta, and shows similarity with another human protein, MLLT2, expressed from a gene at chromosome 4q21 involved in translocations found in acute lymphoblastic leukaemia (ALL) cells14,15. Identifi-cation of this gene will facilitate further studies to determine the role of its product in FRAXE associated mental deficiency.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Verkerk, A.J.M.H. et al. Identification of a gene (FMR-1) containing a CGQ repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 65, 905–914 (1991).

    Article  CAS  Google Scholar 

  2. Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 252, 1711–1714 (1991).

    Article  CAS  Google Scholar 

  3. Oberlé, I. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 252, 1097–1102 (1991).

    Article  Google Scholar 

  4. Yu, S. et al. Fragile-X syndrome: unique genetics of the heritable unstable element. Am. J. Hum. Genet. 50, 968–980 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Knight, S.J.L. et al. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell. 74, 127–134 (1993).

    Article  CAS  Google Scholar 

  6. Parrish, J.E. et al. Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nature Genet. 8, 229–235 (1994).

    Article  CAS  Google Scholar 

  7. Jones, C. et al. Physical linkage of the fragile site FRA11B and a Jacobsen syndrome chromosome deletion breakpoint in 11q23.3. Hum. Mol. Genet. 3, 2123–2130 (1994).

    Article  CAS  Google Scholar 

  8. Nancarrow, J.K. et al. Molecular basis of p(CCG)n repeat instability at the FRA16A fragile site locus. Hum. Mol. Genet. 4, 367–372 (1995).

    Article  CAS  Google Scholar 

  9. Sutcliffe, J.S. et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum. Mol. Genet. 1, 397–400 (1992).

    Article  CAS  Google Scholar 

  10. Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 66, 817–822 (1991).

    Article  CAS  Google Scholar 

  11. Hamel, B.C.J. et al. Segregation of FRAXE in a large family: Clinical, pyschometric, cytogenetic and molecular data. Am. J. Hum. Genet. 55, 923–931 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Knight, S.J.L. et al. Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap. Am. J. Hum. Genet. 55, 81–86 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Mulley, J.C. et al. FRAXE and mental retardation. J. Med. Genet. 32, 162–169 (1995).

    Article  CAS  Google Scholar 

  14. Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to drosophila trithorax, to the AF–4 gene. Cell. 71, 701–708 (1992).

    Article  CAS  Google Scholar 

  15. Morrissey, J. et al. A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias. Blood. 81, 1124–1131 (1993).

    CAS  PubMed  Google Scholar 

  16. Buckler, A.J. et al. Exon amplification: a strategy to isolate mammaliangenes based on RNA splicing. Proc. Natl. Acad. Sci. USA 88, 4005–4009 (1991).

    Article  CAS  Google Scholar 

  17. Lovett, M., Kere, J. & Hinton, L.M. Direct selection: a method for the isolation of cDNAs encoded by large genomic regions. Proc. Na tl. Acad. Sci. USA 88, 9628–9632 (1991).

    Article  CAS  Google Scholar 

  18. Parimoo, S., Patanjali, S.R., Shukla, H., Chaplin, D.D. & Weissman, S.M., cDNA selection: efficient PCR approach for the selection of cDNAs encoded in large chromosomal DNA fragments. Proc. Na tl. Acad. Sci. USA 88, 9623–9627 (1991).

    Article  CAS  Google Scholar 

  19. Timms, K.M. et al. 130 kb of DNA sequence reveals two new genes and a regional duplication distal to the human iduronate-2 sulfatase locus. Genome Res. 5, 71–78 (1995).

    Article  CAS  Google Scholar 

  20. Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl. Acad. Sci. USA 88, 11261–11265 (1991).

    Article  CAS  Google Scholar 

  21. Land, H., Grez, M., Hauser, H., Lindenmaier, W. & Schutz, G. 5′–terminal sequences of eucaryotic mRNA can be cloned with high efficiency. Nucl. Acids Res. 9, 2251–2266 (1981).

    Article  CAS  Google Scholar 

  22. Biondi, A. et al. Detection of ALL-1 /AF4 fusion transcript by reverse transcription-polymerase chain reaction for diagnosis and monitoring of acute leukemias with the t(4;11) translocation. Blood. 82, 2943–2947 (1993).

    CAS  PubMed  Google Scholar 

  23. Eichler, E.E. et al. Evolution of the cryptic FMR1 CGG repeat. Nature Genet. 11, 301–308 (1995).

    Article  CAS  Google Scholar 

  24. Sambrook, J., Fritsch, E.S. & Maniatis, T., A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1989).

  25. Gecz, J., Gedeon, A.K., Sutherland, G.R. & Mulley, J.C. Cloning of FMR2: A gene associated with FRAXE mental retardation. Nature Genet. 13, 105–108 (1996).

  26. Gedeon, A.K. et al. Overlapping submicroscopic deletions in Xq28 in two unrelated boys with developmental disorders: identification of a gene near FRAXE. Am. J. Hum. Genet. 58, 907–914 (1995).

    Google Scholar 

  27. Civitello, A.B., Richards, S. & Gibbs, R.A. A simple protocol for the automation of DNA cycle sequencing reactions and polymerase chain reactions. DNA Seq. 3, 17–23 (1992).

    Article  CAS  Google Scholar 

  28. Munroe, D.J. et al. Systematic screening of an arrayed cDNA library by PCR. Proc. Natl. Acad. Sci. USA 92, 2209–2213 (1995).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gu, Y., Shen, Y., Gibbs, R. et al. Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nat Genet 13, 109–113 (1996). https://doi.org/10.1038/ng0596-109

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0596-109

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing