Infulence of DM Locus on a Distant Gene (FCGRT) in Myot*

描述（由申请人提供）：强直性肌营养不良（DM）是由 扩增的三核苷酸重复，存在于3'非翻译区， DM蛋白肌紧张素激酶（DMPK）mRNA。经过多次调查， 似乎DM综合征是多种机制影响的结果， 不同的基因：（i）重复对蛋白质净表达的影响， DMPK，（ii）含三核苷酸重复序列的mRNA本身对细胞的影响 	或核功能，以及（iii）重复对染色体的影响 这个地区的结构。该研究提案涉及到进一步的潜力 机制：DM疾病位点对远端基因的长期影响， 特别是FCGRT。FCGRT基因编码FcRB的重链、IgG的重链和IgG的重链。 一种在血管内皮细胞中表达的保护受体α， 内吞的IgG抗体。保护机制被压低 在强直性肌营养不良中，与FcRB;受体的低表达相容。 FCGRT已被定位到与DM基因座相同的染色体带（19q13.3）， 但它距离我们有4百万光年长期影响可能仅限于 FCGRT发生在同一条染色体上（顺式），或可能同时发生在两条染色体上 染色体（反式）在受影响的个人。IgG丢失程度 保护与FCGRT表达的一半相容，这将是 与单等位基因抑制兼容。DM和FCGRT的存在 基因在同一条染色体上表明，它们的共定位可能是 超过巧合（p=0.003），即，有一种顺式机制 DM抑制FCGRT基因。如果机制是顺式的，那就意味着一种不寻常的， 可能是DM染色体上的一种新型的长距离相互作用， 例如RNA“涂染”，类似于Xist诱导的X染色体失活。 对于特定的目标，我们建议：证明FCGRT抑制作为 糖尿病患者IgG高钙血症的机制，以确定FCGRT是否 抑制是通过顺式或反式机制，开始阐明分子 这些机制的基础。了解DM患者FCGRT抑制的方法 可能会提出新的研究方向， DM的表型可以解释。

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.