Evidence That Paternal Expression of the ε-Sarcoglycan Gene Accounts for Reduced Penetrance in Myoclonus-Dystonia

Abstract

Myoclonus-dystonia (M-D) is a movement disorder characterized by rapid muscle contractions and sustained twisting and repetitive movements and has recently been associated with mutations in the epsilon-sarcoglycan gene (SGCE). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmission, suggesting a putative maternal imprinting mechanism. We present an apparently sporadic M-D case and two patients from an M-D family with seemingly autosomal recessive inheritance. In both families, we detected an SGCE mutation that was inherited from the patients' clinically unaffected fathers in an autosomal dominant fashion. Whereas, in the first family, RNA expression studies revealed expression of only the mutated allele in affected individuals and expression of the normal allele exclusively in unaffected mutation carriers, the affected individual of the second family expressed both alleles. In addition, we identified differentially methylated regions in the promoter region of the SGCE gene as a characteristic feature of imprinted genes. Using a rare polymorphism in the promoter region in a family unaffected with M-D as a marker, we demonstrated methylation of the maternal allele, in keeping with maternal imprinting of the SGCE gene. Loss of imprinting in the patient with M-D who had biallelic expression of the SGCE gene was associated with partial loss of methylation at several CpG dinucleotides.

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…Loss of methylation on the maternally imprinted gene ε-sarcoglycan causes myoclonus dystonia, a disease characterized by uncontrolled muscle contractions and repetitive movements (94). In mice and sheep, aberrant activation of the imprinted Dlk1-Dio3 cluster is responsible for the callipyge phenotype, an inherited skeletal muscle hypertrophy (95).…”

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…Mutations have been identified in the epsilon-sarcoglycan gene (SGCE, DYT11) in many individuals [12]. In humans, almost exclusively paternal SGCE alleles are transcribed, whereas maternal alleles appear to be inactivated by promoter methylation [13,14]. Consequently, clinical symptoms of DYT11 are absent in over 95% of patients who inherited a SGCE mutation from their mother.…”

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

“…13 Understanding the exclusively neurological phenotype of the disease is still a major challenge. SGCE is an imprinted gene, 14,15 meaning that a loss of function mutation in the expressed allele will be dominant. All reported mutations behave as null alleles, as they result in premature stop codons and are predicted to lead to nonsensemediated decay.…”

“…The region amplified (nucleotide position À1148 to À773 relative to the start ATG) contains 25 CpG sites and has been shown to be differentially methylated. 14 One microgram of genomic DNA was chemically modified with sodium bisulfite using the EZ Methylation kit (Zymo Research, Orange, CA, USA) and amplified in the presence of ResoLight HRM dye (Roche Diagnostics, Almere, the Netherlands). Both methylated and unmethylated strands were amplified.…”