Human Molecular Genetics, Vol 7, 1207-1214, Copyright © 1998 by Oxford University Press
RJ Lemmers, SM van der Maarel, JC van Deutekom, MJ van der Wielen, G Deidda, HG Dauwerse, J Hewitt, M Hofker, E Bakker, GW Padberg and RR Frants
The autosomal dominant myopathy facioscapulohumeral muscular dystrophy
(FSHD) is causally related to a short Eco RI 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.
ARTICLES
Inter- and intrachromosomal sub-telomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis
MGC Department of Human Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2300 RA Leiden, The Netherlands.
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