A Unifying Genetic Model for FSHD - Review

Faculty of 1000 Biology |
A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy.
By Dr. Jane Hewitt

This publication gives significant insight into the fascinating and unique molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD). The causative mutation has been known for almost 20 years to be a deletion in a tandem DNA array (D4Z4) encoding a putative homeodomain protein (DUX4), but why the deletion results in FSHD has been unclear and hotly debated. D4Z4 deletions only cause FSHD if they occur on particular 4q haplotypes that are termed permissive. Now, Lemmers et al., using a combination of high resolution haplotyping and analysing patients with atypical but informative genetic architectures, provide a plausible and intriguing model for FSHD. They show that D4Z4 deletions allow inappropriate generation of a transcript (DUX4) from the distal D4Z4 repeat that utilises a non-canonical polyA signal in an adjacent stretch of beta-satellite DNA, stabilising the mRNA.

The FSHD mutation was first identified in 1992 as a deletion within the D4Z4 tandem DNA array at chromosome 4q35 {1}. This polymorphic array contains 12-150 copies of a 3.3kb DNA repeat in unaffected individuals; in FSHD patients, the number of repeat units is reduced to about 10 or fewer. Although the potential for this array to encode a homeodomain protein was recognised almost immediately {2}, it proved difficult to find evidence that a transcript or protein was produced. Consequently, many researchers proposed that the D4Z4 deletions altered the chromatin structure of this region, affecting the expression of genes proximal to the array. Although there were some data that supported this position effect model, many other studies failed to replicate these findings. Recently, several groups identified transcriptional activity from D4Z4 {3,4} and the DUX4 open reading frame was shown to be evolutionarily conserved {5}; D4Z4 has for several years been known not to be junk DNA or a dead gene. Together with data showing that only some 4q haplotypes are permissive for the disease {6}, these findings shifted focus back to a direct role for the D4Z4 repeat in FSHD. Epigenetic changes in D4Z4 chromatin that were specific for FSHD were recently identified {7}. Here, Lemmers et al. provide a model that is consistent with all these previous studies on D4Z4. Like any good paper, this one raises further questions. Lemmers et al. previously reported that one 4q haplotype (termed 4qA166) is non-permissive for FSHD {6}. Here, they do not report whether the polyA signal is absent in this non-permissive haplotype. A subset of FSHD patients (termed phenotypic FSHD or FSHD2) do not have D4Z4 deletions but do show similar epigenetic changes within the array. It will be important to test whether these patients also show inappropriate activation of DUX4 mRNA. Finally, this polyadenylation signal is not essential for normal DUX4 function since approximately 25% of the population is homozygous for 4qB haplotypes that lack this sequence. Therefore, the relationship between normal DUX4 function and FSHD remains to be resolved. NB - Jane Hewitt is an author on refs {1,2,5}.

References: {1} Wijmenga et al. Nature Genet 1992, 2:26-30 [PMID:1363881]. {2} Hewitt et al. Hum Mol Genet 1994, 3:1287-95 [PMID:7987304]. {3} Dixit et al. Proc Natl Acad Sci USA 2007, 104:18157-62 [PMID:17984056]. {4} Snider et al. Hum Mol Genet 2009, 18:2414-30 [PMID:19359275]. {5} Clapp et al. Am J Hum Genet 2007, 81:264-79 [PMID:17668377]. {6} Lemmers et al. Am J Hum Genet 2007, 81:884-94 [PMID:17924332]. {7} Zeng et al. PLoS Genet 2009, 5:e1000559 [PMID:19593370].