THE EVOLUTIONARY DISTRIBUTION AND STRUCTURAL ORGANIZATION OF THE HOMEOBOX-CONTAINING REPEAT D4Z4 INDICATES A FUNCTIONAL-ROLE FOR THE ANCESTRAL COPY IN THE FSHD REGION

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tand em array of 3.2 kb repeats adjacent to the telomere of 4q, These repea ts are also present in other locations in the human genome, including the short arms of all the acrocentric chromosomes. Here, we examine tw o models for the role of this repeat in FSHD, First, because of the ex tensive similarity between the 3.2 kb repeats on 4q and those adjacent to rDNA on the acrocentric chromosomes, we investigated whether the F SHD region on 4q is involved in sub-nuclear localization, specifically to the nucleolus, The results likely exclude any involvement of nucle olar 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 evol utionary conservation of the repeat and a double homeodomain sequence within the repeat in a variety of primate species. The genomic organiz ation of the 3.2 kb repeat in humans, great apes and lower primates id entified the FSHD-associated repeat on chromosome 4q as the likely anc estral copy, The sequence of the rhesus monkey double homeodomain reve als significant sequence identity with the human 4q sequence. These re sults strongly suggest a functional role for a component of the FSHD-a ssociated repeat.