DM Locus in Myotonic Dystrophy

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DESCRIPTION (provided by applicant): Myotonic dystrophy (DM) is caused by an expanded trinucleotide repeat that is present in the 3' untranslated region of the mRNA of DM protein myotonin kinase (DMPK). After many investigations, it appears that the DM syndrome is a result of diverse mechanisms influencing different genes: (i) effects of the repeat on the net expression of protein of DMPK, (ii) effects of the trinucleotide-repeat-containing mRNA itself on cell 	or nuclear functions, and (iii) effects of the repeat on the chromosomal structure in this region. The research proposal addresses a further potential mechanism: long-range effects of the DM disease locus on a distant gene, specifically FCGRT. The'FCGRT gene encodes the heavy chain of the FcRB, the IgG A protection receptoralpha expressed in vascular endothelial cells that rescues endocytosed IgG antibody from catabolism. The protection mechanism is depressed in myotonic dystrophy, compatible with underexpression of the FcRB; receptor. FCGRT has been mapped to the same chromosomal band (19ql3.3) as the DM locus, but it is 4 megabases distant. The long-range effects may be confined to the FCGRT on the same chromosome (cis) or may be experienced by FCGRT on both chromosomes (trans) in affected individuals. The degree of loss of IgG protection is compatible with half as much expression of FCGRT, that would be compatible with a monoallelic suppression. The presence of the DM and FCGRT genes in the same chromosomal band suggests that their co-localization may be more than coincidental (p=0.003), i.e., that there is a cis-mechanism by which DM suppresses the FCGRT gene. If the mechanism is cis, it implies an unusual, and 	perhaps novel, type of long-range interaction on the DM chromosome, such as RNA "painting" in analogy to Xist-induced X chromosome inactivation. For specific aim , we propose: to demonstrate FCGRT suppression as the mechanism of IgG hypericatabolism in DM, to establish whether the FCGRT suppression is by a cis or trans mechanism, to begin to elucidate the molecular basis for these mechanisms. Understanding the means of FCGRT suppression in DM may suggest new directions of research by which the multisystem/multigene phenotype of DM may be explained.