Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene. Issue 2 (12th January 2021)

• Record Type: Journal Article
• Authors: Lemmers, Richard J L F; van der Vliet, Patrick J; Blatnik, Ana; Balog, Judit; Zidar, Janez; Henderson, Don; Goselink, Rianne; Tapscott, Stephen J; Voermans, Nicol C; Tawil, Rabi; Padberg, George W A M; van Engelen, Baziel GM; van der Maarel, Silvère M
• Is Part Of: Journal of medical genetics. Volume 59:Issue 2(2022)
• Page Start: 180
• Page End: 188
• Publication Date: 2021-01-12
• Subjects: gene rearrangement -- neuromuscular diseases -- gene expression -- diagnosis -- genetic research; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2020-107041
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Facioscapulohumeral 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. Method: Detailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals. Results: Identification 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. Conclusion: This 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.