[Genetic analysis of facioscapulohumeral muscular dystrophy (FSHD)]

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder which is characterized by progressive weakness and atrophy of the facial, shoulder-girdle and upper arm muscles, and occasional subsequent pelvic-girdle and lower limb involvement. The gene responsible for FSHD has been localized to chromosome 4q35-qter, although a few 4q-unlinked families are known. To examine FSHD-associated DNA rearrangements in the Japanese population, we performed Southern blot analysis of the genomic DNA, using the p13E-11 and pFR-1 probes. Most of the Japanese FSHD patients (> 95%) had specific smaller (< 28 kb) EcoRI fragments which cosegregated with the disease. Restriction enzyme maps of the polymorphic EcoRI fragment detected by the probes have revealed that the disease occurs due to a deletion of the integral numbers of the 3.3kb KpnI tandemly repeated fragments (D4Z4) which contain homeobox-like sequences. Indeed, we cloned and characterized the FSHD-associated EcoRI fragments (the shortest fragment identified to date: 10kb) from two severely affected patients (unrelated). The 10kb fragment were identical and contained only one 3.3kb KpnI repeat unit. Although we still do not know whether truncation deletion of the D4Z4 region could produce FSHD directly or indirectly (position effect), we now beginning to understand FSHD. In the next step, FSHD gene products (mRNA and protein) responsible for the disease should be investigated.