Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene

Abstract

BackgroundFacioscapulohumeral dystrophy (FSHD) is an inherited muscular dystrophy clinically characterised by muscle weakness starting with the facial and upper extremity muscles. A disease model has been developed that postulates that failure in somatic repression of the transcription factor DUX4 embedded in the D4Z4 repeat on chromosome 4q causes FSHD. However, due to the position of the D4Z4 repeat close to the telomere and the complex genetic and epigenetic aetiology of FSHD, there is ongoing debate about the transcriptional deregulation of closely linked genes and their involvement in FSHD.MethodDetailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals.ResultsIdentification of two FSHD families in which the disease is caused by repeat contraction and DUX4 expression from chromosome 10 due to a de novo D4Z4 repeat exchange between chromosomes 4 and 10. We show that the genetic lesion causal to FSHD in these families is physically separated from other candidate genes on chromosome 4. We demonstrate that muscle cell cultures from affected family members exhibit the characteristic molecular features of FSHD, including DUX4 and DUX4 target gene expression, without showing evidence for transcriptional deregulation of other chromosome 4-specific candidate genes.ConclusionThis study shows that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q. These findings provide further evidence that DUX4 derepression is the dominant disease pathway for FSHD. Hence, therapeutic strategies should focus on DUX4 as the primary target.

Systemic delivery of a DUX4-targeting antisense oligonucleotide to treat facioscapulohumeral muscular dystrophy

“…Previous studies showed that DUX4c is upregulated in FSHD myocytes and that it may disturb myogenesis and facilitate DUX4 toxicity, 38 , 39 although in one FSHD family a proximal deletion at D4Z4 including the DUX4c gene was identified and patients have been diagnosed with FSHD linked to chromosome 10q where no complete DUX4c gene resides, suggesting that DUX4c is dispensable for FSHD pathogenesis. 38 , 40 , 41 The DUXO gene may have a function in early development. 42 We therefore do not expect that reducing DUX4c and DUXO transcript levels in skeletal muscles will cause adverse effects; however, we could not assess this in the current study because DUX4c and DUXO are absent from the mouse genome.…”

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

“…Very rare cases (2 families) of FSHD associated with a reduced number of D4Z4 repeats located in the subtelomere of 10q from de novo D4Z4 repeat exchange between chromosomes 4 and 10, indicate that D4Z4 units encoding DUX4 and a poly(A) signal are essential for pathology. However, the FRG2 gene remains present at 10q in these patients and is upregulated, and so involvement of FRG2 in pathology cannot be excluded (Lemmers et al , 2010 ; Lemmers et al , 2021 ). The potential roles of FRG1 and FRG2 are further complicated as both are direct targets genes of DUX4 (Thijssen et al , 2014 ; Ferri et al , 2015 ).…”

Guidelines for genetic testing of muscle and neuromuscular junction disorders

“…55 Contraction of these repeats is nearly always benign. 56 Caution should therefore be exercised in interpreting the significance of D4Z4 contractions in translocation carriers. Yet other patients carry on chromosome 4 hybrid repeats consisting of both chromosome 4-type and 10-type repeats, and contraction of these repeats can lead to FSHD.…”

“…Southern blot methodology used for FSHD testing can distinguish between them, but approximately 20% of the population carry a translocation between chromosomes 4q and 10q, resulting in the presence of chromosome 4–type D4Z4 repeats on chromosome 10 55 . Contraction of these repeats is nearly always benign 56 . Caution should therefore be exercised in interpreting the significance of D4Z4 contractions in translocation carriers.…”