Human Molecular Genetics, Vol 5, 1567-1575, Copyright © 1996 by Oxford University Press
ST Winokur, U Bengtsson, JC Vargas, JJ Wasmuth, MR Altherr, B Weiffenbach and SJ Jacobsen
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant
neuromuscular disease that has been linked to deletions within a tandem
array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are
also present in other locations in the human genome, including the short
arms of all the acrocentric chromosomes. Here, we examine two models for
the role of this repeat in FSHD. First, because of the extensive similarity
between the 3.2 kb repeats on 4q and those adjacent to rDNA on the
acrocentric chromosomes, we investigated whether the FSHD region on 4q is
involved in sub-nuclear localization, specifically to the nucleolus. The
results likely exclude any involvement of nucleolar localization in the
development of FSHD. Second, we investigated a model that suggests that a
functional gene may be buried within the tandem array of 3.2 kb repeats.
Toward this end, we evaluated the evolutionary conservation of the repeat
and a double homeodomain sequence within the repeat in a variety of primate
species. The genomic organization of the 3.2 kb repeat in humans, great
apes and lower primates identified the FSHD-associated repeat on chromosome
4q as the likely ancestral copy. The sequence of the rhesus monkey double
homeodomain reveals significant sequence identity with the human 4q
sequence. These results strongly suggest a functional role for a component
of the FSHD-associated repeat.
ARTICLES
The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region [published erratum appears in Hum Mol Genet 1997 Mar;6(3):502]
Department of Biological Chemistry, University of California, Irvine 92717, USA.
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