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Cause of FSHD2 found
18 December 2012

Dr. Richard LemmersScientists from the department of Human Genetics at the Leiden University Medical Center in collaboration with research groups from Seattle, Rochester, Nice, Amsterdam and Nijmegen recently have found the cause of facioscapulohumeral muscular dystrophy type 2 (FSHD2) [Lemmers et al., Nature Genetics 2012].

FSHD is a progressive muscular dystrophy that mainly involves the facial, shoulders and upper arms muscles and affects approximately half a million individuals world wide. Two years ago the same group showed that ectopic expression of the germline transcription factor DUX4 in muscle cells is causing FSHD. In control individuals, the DUX4 retrogene is organized in a multicopy fashion which is a natural mechanism to repress retrogene expression by tight chromatin packaging and DNA methylation in somatic cells. In most FSHD patients the number of DUX4 gene copies in the array is reduced which obstructs the repression mechanism and releases DUX4 (FSHD1).

FSHD2 patients do not show a reduction of the DUX4 gene copy array and for these families there was no genetic test available. Yet, both FSHD1 and FSHD2 patients show DUX4 expression in myotubes. More detailed analysis of patients with FSHD2 demonstrated a general loss of DNA methylation at the promoter of the DUX4 gene indicative of gene activation. Furthermore, this DNA hypomethylation trait was shown to be transmitted in a dominant fashion. Therefore, we applied next generation sequencing and found that mutations in the SMCHD1 gene were responsible for at least 80% of the FSHD2 families. The Smchd1 gene was first identified in mice, where it was already shown to play an important role in the regulation of gene expression by the CpG methylation. This finding enables genetic testing for FSHD2 families and it might open new roads to therapy.

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