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The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: Implications for a role of chromatin structure in the pathogenesis of the disease

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Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant form of muscular dystrophy. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. Recently, a probe was identified that detects anEcoRI fragment length polymorphism which segregates with the disease in most FSHD families. Within theEcoRI fragment lies a tandem array of 3.2 kb repeats. In several familial cases and four independent sporadic FSHD mutations, the variation in size of theEcoRI fragment was due to a decrease in copy number of the 3.2 kb repeats. To gain further insight into the relationship between the tandem array and FSHD, a single 3.2 kb repeat unit was characterized. Fluorescencein situ hybridization (FISH) demonstrates that the 3.2 kb repeat cross-hybridizes to several regions of heterochromatin in the human genome. In addition, DNA sequence analysis of the repeat reveals a region which is highly homologous to a previously identified family of heterochromatic repeats, LSau. FISH on interphase chromosomes demonstrates that the tandem array of 3.2 kb repeats lies within 215 kb of the 4q telomere. Together, these results suggest that the tandem array of 3.2 kb repeats, tightly linked to the FSHD locus, is contained in heterochromatin adjacent to the telomere. In addition, they are consistent with the hypothesis that the gene responsible for FSHD may be subjected to position effect variegation because of its proximity to telomeric heterochromatin.

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Authors and Affiliations

  1. Department of Biological Chemistry, University of California, Irvine, CA, USA

    Sara T. Winokur, Ulla Bengtsson, Rachelle P. Markovich, John J. Wasmuth & Michael R. Altherr

  2. Department of Pediatrics, University of Iowa Hospitals and Clinics, 216 MRC, 52242, Iowa City, IA, USA

    Julie Feddersen, Kathy D. Mathews, Holly Bailey, Jeffrey C. Murray & Brian C. Schutte

  3. Collaborative Research Inc., Waltham, NA, USA

    Barbara Weiffenbach

  4. Genomics and Structural Biology Group, LANL, Los Alamos, NM, USA

    Michael R. Altherr

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  1. Sara T. Winokur
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  2. Ulla Bengtsson
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  3. Julie Feddersen
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  4. Kathy D. Mathews
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  5. Barbara Weiffenbach
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  6. Holly Bailey
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Correspondence to Brian C. Schutte.

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Winokur, S.T., Bengtsson, U., Feddersen, J. et al. The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: Implications for a role of chromatin structure in the pathogenesis of the disease. Chromosome Res 2, 225–234 (1994). https://doi.org/10.1007/BF01553323

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