Journal Article

Inter-and Intrachromosomal Sub-Telomeric Rearrangements on 4q35: Implications for Facioscapulohumeral Muscular Dystrophy (FSHD) Aetiology and Diagnosis

Richard J. L. F. Lemmers, Silvère M. van der Maarel, Judith C. T. van Deutekom, Michiel J. R. van der Wielen, Giancarlo Deidda, Hans G. Dauwerse, Jane Hewitt, Marten Hofker, Egbert Bakker, George W. Padberg and Rune R. Frants

in Human Molecular Genetics

Volume 7, issue 8, pages 1207-1214
Published in print August 1998 | ISSN: 0964-6906
Published online August 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.8.1207
Inter-and Intrachromosomal Sub-Telomeric Rearrangements on 4q35: Implications for Facioscapulohumeral Muscular Dystrophy (FSHD) Aetiology and Diagnosis

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The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD) is causally related to a short EcoRI fragment detected by probe p13E-11. This remnant fragment is the result of a deletion of an integral number of tandemly arrayed 3.3 kb repeat units (D4Z4) on 4q35. Despite intensive efforts, no transcribed sequences have been identified within this array. Previously, we have shown that these repeats on 4q35 have been exchanged for a similar highly homologous repeat locus on 10q26 in 20% of the population and that a short chromosome 10-like array on 4q35 also results in FSHD. Here, we describe the hybrid structure of some of these repeat arrays, reflecting additional sub-telomeric instability. In three healthy individuals carrying a 4-like repeat on chromosome 10 or vice versa, one repeat array was shown to consist of hybrid clusters of 4-derived and 10-derived repeat units. Moreover, employing pulsed field gel electrophoresis analysis, we identified two unrelated individuals carrying deletions of a chromosomal segment (p13E-11) proximal to the repeat locus. These deletions were not associated with FSHD. In one of these cases, however, an expansion of the deletion into the repeat array was observed in one of his children suffering from FSHD. These data provide additional evidence for instability of this sub-telomeric region and suggests that the length of the repeat, and not its intrinsic properties, is crucial to FSHD. Moreover, they are in agreement with the hypothesis that FSHD is caused by a position effect in which the repeat structure influences the expression of genes nearby. Therefore, the region deleted proximal to the repeat locus in healthy individuals can be instrumental to refine the critical region for FSHD1.

Journal Article.  5161 words.  Illustrated.

Subjects: Genetics and Genomics

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