Molecular analysis of the facioscapulohumeral muscular dystrophy (FSHD) associated DNA rearrangements in the South African population
Van der Merwe, Annelize
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Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited disorder of muscle after Duchenne and Myotonic dystrophy, with a prevalence of at least 1 in 20,000. FSHD is characterised by progressive weakening and atrophy of the face, shoulder-girdle and upper arm, although other skeletal muscles may also become involved with progression of the disorder. The FSHD phenotype segregates as an autosomal dominant trait. Linkage was established to chromosome 4q35 in 1990. A deletion of an integral number of 3.3 kb repeats, localised at the D4Z4 locus, was reported to cause FSHD. Translocation events between chromosomes 4q35 and 10q26, also harbouring similar 3.3 kb repeat units, have been detected via the presence of Bln I sites within the 10q26 repeats. In this study the D4Z4 locus was investigated for the first time on a molecular level in the Black South African and Khoi-San populations. The translocation frequency between chromosomes 4q35 and 10q26 was evaluated via the Bln I / Bgl II dosage test. Haplogroup analysis was utilised to determine the relative evolutionary age of the translocation event. The Eurasian population harbours an excess of 4-on-10 fragments. This excess was postulated to be a significant, if not the major predisposing factor that gives rise to the FSHD-type deletion. The predisposed population thus has individuals that are more susceptible to FSHD. An enrichment of 10-on4 was observed in the Black South African population. It was postulated that this enrichment is an epigenetic protective factor for FSHD, since no FSHD case has been reported in this population to date. It is further hypothesised that the absence of FSHD cases in this population is due to this enrichment. As a consequence, the excess and enrichment of specific translocation profiles in different populations is an additional factor that affects the aetiology of FSHD within specific populations.