Genetic Story of Common Muscular Dystrophy Progresses

An international group of researchers has unlocked another door to understanding the cause of facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy.* Reporting electronically in Science, Lemmers and colleagues add to the long-known genetics of the autosomal dominant disease.

In 1992, it was discovered that the molecular defect in FSHD localizes to the distal portion of the long arm of chromosome 4 (specifically 4q35), in which a dormant repetitive element, D4Z4, is truncated. Only individuals with 1-10 D4Z4 repeats can acquire FSHD (normal individuals have 11-100 repeats). It was further learned that the number of D4Z4 repeats in people with FSHD correlates inversely with the age of onset and disease severity; however, it was also observed that clinical manifestations among family members with the same deletion can differ. (For a free review of FSHD and its genetics, circa 2008, go here.)

The Science authors showed that, somehow, the truncated D4T4 area in FSHD patients changes the chromosomal configuration, which allows for the transcription of an internal homeobox gene, DUX4. But FSHD patients also carry specific single nucleotide polymorphisms (SNPs) distal to the D4Z4 region that encode for a transcript-stablizing poly-A tail. Therefore, in people with FSHD, the transcribed DUX4 gene, which might otherwise be chewed up, is stabilized by being polyadenylated.

What the product of the polyadenylated DUX4 transcript is and what it does remain to be discovered.

* Affecting 1 in 20,000.