Abstract
Facioscapulohumeral muscular dystrophy is caused by incomplete repression of the transcription factor DUX4 in skeletal muscle as a consequence of D4Z4 macrosatellite repeat contraction in chromosome 4q35 (FSHD1) or variants in genes encoding D4Z4 chromatin repressors (FSHD2). A clinical hallmark of FSHD is variability in onset and progression suggesting the presence of disease modifiers. A well-known cis modifier is the polymorphic DUX4 polyadenylation signal (PAS) that defines FSHD permissive alleles: D4Z4 chromatin relaxation on non-permissive alleles which lack the DUX4-PAS cannot cause disease in the absence of stable DUX4 mRNA. We have explored the nature and relevance of a common variant of the major FSHD haplotype 4A161, which is defined by 1.6 kb size difference of the most distal D4Z4 repeat unit. While the short variant (4A161S) has been extensively studied, we demonstrate that the long variant (4A161L) is relatively common in the European population, is capable of expressing DUX4, but that DUX4 mRNA processing differs from 4A161S. While we do not find evidence for a difference in disease severity between FSHD carriers of an 4A161S or 4A161L allele, our study does uncover biallelic DUX4 expression in FSHD2 patients. Compared to control individuals, we observed an increased frequency of FSHD2 patients homozygous for disease permissive alleles, and who are thus capable of biallelic DUX4 expression, while SMCHD1 variant carriers with only one permissive allele were significantly more often asymptomatic. This suggests that biallelic DUX4 expression lowers the threshold for disease presentation and is a modifier for disease severity in FSHD2.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Facioscapulohumeral dystrophy (FSHD; OMIM 158900 & 158901) is one of the more common hereditary myopathies characterized by a descending pattern of muscle weaknessFSHD is caused by incomplete repression of the DUX4 retrogene (OMIM 606009) in skeletal muscle [2,3,4,5,6]
We performed immunofluorescence analysis on myotube cultures derived from FSHD1 and FSHD2 patients, in which the pathogenic repeat is either on a 4A161S or 4A161L background
FSHD is clinically characterized by substantial variability in onset and progression of the disease, even within FSHD1 families where individuals at risk carry the same D4Z4 repeat array contraction [34,35,36]
Summary
FSHD is caused by incomplete repression of the DUX4 retrogene (OMIM 606009) in skeletal muscle [2,3,4,5,6]. DUX4 is a transcription factor normally expressed in the luminal cells of the testis and in cleavage stage embryos but repressed in somatic tissue such as skeletal muscle [7,8,9,10]. A copy of the DUX4 retrogene is embedded within each unit of the D4Z4 macrosatellite repeat array on chromosome 4, which is polymorphic in repeat number and normally varies between 8–100 copies [3, 4, 16, 17]. A prominent difference between FSHD1 and FSHD2 is that while in FSHD1 the D4Z4 chromatin changes are restricted to the contracted D4Z4 array, in FSHD2 these chromatin changes can be b
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