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Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats

Nature Genetics volume 16, pages 96–99 (1997)Cite this article

Abstract

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked disorder characterized by contractures, progressive muscle weakness and cardiomyopathy1–3. The emerin gene, located in human Xq28, is approximately 2 kb in length, is composed of 6 exons and falls within a 219-kb region that has been completely sequenced4–6. Immediately centromeric to emerin is the 26-kb filamin gene (FLN1), composed of 48 exons and encoding the actin-binding protein 280 (refs 7,8). Flanking this 48-kb FLN1/emerin region are two large inverted repeats, each 11.3 kb, that exhibit >99% sequence identity6. The high level of genomic detail in this region allowed us to characterize the first complete emerin gene deletion mutation that also involved a partial duplication of the nearby FLN1 gene. This rearrangement could be explained by mispairing of the large inverted repeats, followed by double recombination among one set of mispaired repeats and internal sequences. Furthermore, our characterization of this rare DNA rearrangement revealed a more common result of the mispairing of these large inverted repeats7—recombination contained within the inverted repeats leading to the maintenance of repeat sequence homogeneity and inversion of the 48-kb FLN1/emerin region. The presence of this frequent inversion, found in the heterozygous state in 33% of females, helps to explain the discrepancies observed between the genetic and physical map distances in this region of the X chromosome. It also illustrates the biological insights which can be gleaned by sequencing the human genome.

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References

  1. McKusick, V.A., Mendelian Inheritance in Man (The Johns Hopkin's University Press, Baltimore 1994).

  2. Emery, A.E.H., Emery-Dreifuss Syndrome. J. Med. Genet. 26, 637–641 (1989).

    Article  CAS  Google Scholar 

  3. Hopkins, L.C. & Warren, S.T. in Handbook of Clinical Neurobiology. feds Rowland, Eds & DiMauro, S.) 145–160 (Elsevier, Amsterdam, 1993).

    Google Scholar 

  4. Bione, S. et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nature Genet. 8, 323–327 (1994).

    Article  CAS  Google Scholar 

  5. Bione, S. et al. Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease. Hum. Mol. Genet. 4, 1859–1863 (1995).

    Article  CAS  Google Scholar 

  6. Chen, E.Y. et al. Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DMA betwen the RCP/GCPand G6PD loci. Hum. Mol. Genet. 5, 659–668 (1996).

    Article  CAS  Google Scholar 

  7. Gorlin, J.B. et al. Actin-binding protein (ABP-280) filamin gene (FLN) maps telomeric to the color vision locus (R/GCP) and centromeric to G6PD in Xq28. Genomics 17, 496–497 (1993).

    Article  CAS  Google Scholar 

  8. Patrosso, M.C. et al. The exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280. Genomics 21, 71–76 (1994).

    Article  CAS  Google Scholar 

  9. Roth, D.B., Porter, T.N. & Wilson, J.H. Mechanisms of nonhomologous recombination in mammalian cells. Mol. Cell. Biol. 5, 2599–2607 (1985).

    Article  CAS  Google Scholar 

  10. Woods-Samuels, P., Kazazian, H.H. & Antonarakis, S.E. Nonhomologous recombination in the human genome: Deletions in the human factor VIII gene. Genomics 10, 94–101 (1991).

    Article  CAS  Google Scholar 

  11. Cunningham, C.C. et al. Actin-binding protein requirement for cortical stability and efficient locomotion. Science 255, 325–327 (1992).

    Article  CAS  Google Scholar 

  12. Rossitier, J.P. et al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum. Mol. Genet. 3, 1035–1039 (1994).

    Article  Google Scholar 

  13. Coyne, J.A., Aulard, S. & Berry, A. Lack of underdominance in a naturally occuring pericentric inversion in Drosophila melanogaster and its implications for chromosome evloution. Genetics 129, 791–802 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zetka, M.C. & Rose, A.M. The meiotic behavior of an inversion in Caenorhabditis elegans. Genetics 131, 321–332 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Dresser, M.E., Ewing, D.J., Harwell, S.N., Coody, D. & Conrad, M.N. logous synapsis and reduced crossingover in a heterozygous paracentric inversion in Saccharomyces cerevisae. Genetics 138, 633–647 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ashley, T., Cacheiro, N.L.A., Russell, L.B. & Ward, D.B. Molecular characterization of a pericentric inversion in mouse chromosome 8 implicates telomeres as promoters of meiotic recombination. Chromosoma 102, 112–120 (1993).

    Article  CAS  Google Scholar 

  17. Sashi, V. et al. Molecular analysis of recombination in family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion. Am. J. Hum. Genet. 58, 1231–1238 (1996).

    Google Scholar 

  18. King, M. A dual model for speciation by multiple pericentric inversions. Heredity 68, 437–440 (1992).

    Article  Google Scholar 

  19. Wang, L.H., Collins, A., Lawrence, S., Keats, B.J. & Morton, N.E. Integration of gene maps: Chromosome X. Genomics 22, 590–604 (1994).

    Article  Google Scholar 

  20. Rogner, U.C. et al. A YAC clone map spanning 7.5 megabases of human chromosome band Xq28. Hum. Mol. Genet. 3, 2137–2146 (1994).

    Article  CAS  Google Scholar 

  21. Willard, H.F. et al. Report of the fifth international workshop on human X chromosome mapping 1994. Cytogenet Cell Genet. 67, 296–328 (1994).

    CAS  Google Scholar 

  22. Dausset, J. et al. Centre d'Etude du Polymorphisme Humaine (CEPH): Collaborative genetic mapping of the human genome. Genomics 6, 575–577 (1990).

    Article  CAS  Google Scholar 

  23. Filosa, S. et al. G6PD haplotypes spanning Xq28 from F8C to Red/Green color vision. Genomics 17, 6–14 (1993).

    Article  CAS  Google Scholar 

  24. Yen, P.H. et al. Frequent deletions of the human X chromosome distal short arm result from recombination between low copy repetitive elements. Cell 61, 603–610 (1990).

    Article  CAS  Google Scholar 

  25. Pentao, L., Wise, C.A., Chinault, A.C., Patel, P.I. & Lupski, J. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 kb monomer unit. Nature Genet. 2, 292–300 (1992).

    Article  CAS  Google Scholar 

  26. Lakich, D., Kazazian, H.H., Antonarakis, S.E. & Gitschier, J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genet. 5, 236–241 (1993).

    Article  CAS  Google Scholar 

  27. Naylor, J.A. et al. Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum. Mol. Genet. 4, 1217–1224 (1995).

    Article  CAS  Google Scholar 

  28. Parrish, J.E. et al. A muscle-specific DNase l-like gene in human Xq28. Hum. Mol. Genet. 4, 1557–1564 (1995).

    Article  CAS  Google Scholar 

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  1. Howard Hughes Medical Institute and Departments of Biochemistry, Pediatrics, and Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Kersten Small, Jane Iber & Stephen T. Warren

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Correspondence to Stephen T. Warren.

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Small, K., Iber, J. & Warren, S. Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. Nat Genet 16, 96–99 (1997). https://doi.org/10.1038/ng0597-96

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