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. 2002 Dec;71(6):1303-11.
doi: 10.1086/344531. Epub 2002 Nov 20.

Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia

Birgitt Müller  1 , Katja Hedrich, Norman Kock, Natasa Dragasevic, Marina Svetel, Jennifer Garrels, Olfert Landt, Matthias Nitschke, Peter P Pramstaller, Wolf Reik, Eberhard Schwinger, Jürgen Sperner, Laurie Ozelius, Vladimir Kostic, Christine Klein
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Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia

Birgitt Müller et al. Am J Hum Genet. 2002 Dec.

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.

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Figures

Figure 1
Figure 1
Pedigrees of families V and S. A.1 and A.2, Pedigrees with haplotypes in the SGCE region on chromosome 7q21. Affected individuals are shaded in black; unaffected mutation carriers are indicated with a black dot. The mutated allele inherited from each of the fathers is highlighted in gray. B.1 and B.2, Sequences at the gDNA and cDNA levels, with the 966delT in exon 7 and 625insG in exon 5 (reverse strand is shown) indicated with arrows. C.1 and C.2, Melting curves generated with gDNA (a) and cDNA (b).
Figure 2
Figure 2
Methylation studies. A, Pedigree of family R, with haplotypes in the SGCE chromosomal region. B, Sequences of two plasmids containing either the paternal (left) or maternal (right) allele of individual II.1 from family R, after bisulfite treatment. The polymorphism is indicated with an arrow. Sequences demonstrate that the maternal allele (with G) was methylated, since several Cs (indicated by asterisks) escaped conversion to Ts. In contrast, the paternal allele was unmethylated. C, Sequence of plasmid 5 of the PromM region derived from the index patient in family S, demonstrating the loss of two methylated Cs (indicated by triangles).
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References

Electronic-Database Information

    1. Center for Medical Genetics, Marshfield Medical Research Foundation, http://research.marshfieldclinic.org/genetics/
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for SGCE [accession number NM_003919])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for SGCE [MIM 604149] and M-D [MIM 159900])

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