Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy

Myotonic dystrophy (DM) is a neuromuscular disorder associated with CTG tri plet repeat expansion in the myotonin protein kinase gene (DMPK), We previo usly proposed a hypothesis suggesting that the expanded CUG repeats sequest er specific RNA-binding proteins and that such a sequestration results in a bnormal RNA processing of several RNAs containing CUG repeats in multiple t issues affected in patients with DM. One of the members of the CUG-binding proteins, CUG-BP, has been identified previously. Here we describe the seco nd member of this family, elav-type ribonucleoprotein (ETR-3), which is hig hly expressed in heart and is able to interact with CUG repeats. Screening of a mouse liver cDNA library with a CUG-BP probe identified two mETR-3 cDN As, Two additional cDNAs from mouse heart were amplified by RT-PCR, These c DNAs differ by several insertions/deletions and might be generated via alte rnative splicing. Mouse ETR-3 has a mel, wt of 50 kDa and displays a high l evel of homology to CUG-BP protein, The organization of the RNA-binding dom ains (RBDs) within the ETR-3 molecule is similar to one within CUG-BP, A st udy of mETR-3 RNA-binding activity showed that the mETR-3 binds to (CUG)(8) repeats. Sequence analysis of mETR-3 indicates the presence of several CUG repeats within the mETR-3 mRNA, Both CUG-BP and mETR-3 bind to mETR-3 mRNA via CUG repeats, suggesting the possible involvement of CUG-BP-like protei ns in the regulation of mETR-3 processing. Analysis of the tissue distribut ion of ETR-3 showed that in human cells, ETR-3 mRNA is highly expressed in heart, but is undetectable in other tissues examined, Our results suggest t he existence of a family of proteins that bind to CUG repeats and might be affected in DM by expansion of CUG repeats.