Alternative titles; symbols
HGNC Approved Gene Symbol: MBNL3
Cytogenetic location: Xq26.2 Genomic coordinates (GRCh38): X:132,369,320-132,490,035 (from NCBI)
MBNL3 belongs to a conserved family of RNA-binding proteins characterized by 2 pairs of C3H-type zinc finger-related motifs. These proteins function as target-specific regulators of pre-mRNA splicing (Ho et al., 2004).
By searching databases for homologs of human MBNL (MBNL1; 606516), followed by 5-prime and 3-prime RACE, Fardaei et al. (2002) cloned human MBNL2 (607327) and MBNL3, which they called MBLL and MBXL, respectively. All 3 human genes show extensive alternative splicing. Northern blot analysis showed that MBNL and MBLL were expressed in many adult human tissues, whereas MBXL was expressed predominantly in placenta.
Myotonic dystrophy (DM1; 160900) is a complex neuromuscular disorder associated with DNA expansion mutations in 2 different genes. In DM1 a CTG repeat in the 3-prime-untranslated region of DMPK (605377) is expanded, whereas in DM2 (602668) an intronic CCTG expansion occurs in the ZNF9 gene (116955). Transcripts containing expanded repeats form foci in the nuclei of DM1 and DM2 cells. Miller et al. (2000) and Mankodi et al. (2001) showed that human proteins related to Drosophila muscleblind colocalized with repeat foci in DM1 and DM2 cells. Fardaei et al. (2002) found that green fluorescent protein-tagged versions of human MBNL, MBLL, and MBXL colocalized with nuclear foci in DM1 and DM2 cells, suggesting that all 3 proteins may play a role in DM pathophysiology.
By expressing fluorescence-tagged proteins in primary chicken skeletal muscle cultures, Ho et al. (2004) showed that human MBNL1, MBNL2, and MBNL3 repressed inclusion of exon 5 in chicken and human cardiac troponin (cTNT, or TNNT2; 191045) minigenes and induced inclusion of exon 11 in a human insulin receptor (IR, or INSR; 147670) minigene. Depletion of MBNL1 in HeLa cells via small interfering RNA promoted exon inclusion in cTNT, exon skipping in IR, and only minimal splicing changes in a clathrin light chain B (CLTB; 118970) minigene. Ultraviolet (UV) crosslinking and scanning mutagenesis studies identified 2 MBNL1-binding sites upstream of cTNT exon 5. Mutations within the MBNL1-binding sites significantly reduced binding by MBNL1 and MBNL3 and eliminated binding by MBNL2. Alignment of the MBNL1-binding sites in chicken and human cTNT revealed a common MBNL-binding motif, YGCU(U/G)Y, where Y represents U or C. Ho et al. (2004) noted that CELF proteins (e.g., BRUNOL1, or TNRC4; 612678) induce inclusion of exon 5 in chicken and human cTNT and exon skipping of human IR exon 11. They proposed that MBNL and CELF proteins function antagonistically to regulate splicing in specific target pre-mRNAs.
Lee et al. (2010) showed that Mbnl3 promoted exclusion of the beta exon from Mef2a (600660) and Mef2d (600663) transcripts in C2C12 mouse muscle cells, which antagonized muscle differentiation. UV crosslinking experiments revealed that Mbnl3 selectively bound to Mef2d intron 7 and silenced beta exon splicing during differentiation. Mutation of cysteines within the 4 C3H motifs of Mbnl3 revealed a critical role of the zinc finger domains in binding RNA. Expression of wildtype Mbnl3 led to a significant decrease in Mef2d transcripts containing the beta exon. Both a mouse cell culture model of myotonic dystrophy and skeletal and cardiac muscle from myotonic dystrophy patients showed elevated expression of MBNL3 mRNA, concomitant with significantly reduced levels of MEF2D transcripts containing the beta exon. Lee et al. (2010) concluded that upregulation of MBNL3 can contribute to the pathology of myotonic dystrophy.
By database analysis, Fardaei et al. (2002) determined that the MBNL3 gene maps to the X chromosome.
Hartz (2012) mapped the MBNL3 gene to chromosome Xq26.2 based on an alignment of the MBNL3 sequence (GenBank AK002178) with the genomic sequence (GRCh37).
Fardaei, M., Rogers, M. T., Thorpe, H. M., Larkin, K., Hamshere, M. G., Harper, P. S., Brook, J. D. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum. Molec. Genet. 11: 805-814, 2002. [PubMed: 11929853] [Full Text: https://doi.org/10.1093/hmg/11.7.805]
Hartz, P. A. Personal Communication. Baltimore, Md. 1/11/2012.
Ho, T. H., Charlet-B, N., Poulos, M. G., Singh, G., Swanson, M. S., Cooper, T. A. Muscleblind proteins regulate alternative splicing. EMBO J. 23: 3103-3112, 2004. [PubMed: 15257297] [Full Text: https://doi.org/10.1038/sj.emboj.7600300]
Lee, K.-S., Cao, Y., Witwicka, H. E., Tom, S., Tapscott, S. J., Wang, E. H. RNA-binding protein muscleblind-like 3 (MBNL3) disrupts myocyte enhancer factor 2 (Mef2) beta-exon splicing. J. Biol. Chem. 285: 33779-33787, 2010. [PubMed: 20709755] [Full Text: https://doi.org/10.1074/jbc.M110.124255]
Mankodi, A., Urbinati, C. R., Yuan, Q.-P., Moxley, R. T., Sansone, V., Krym, M., Henderson, D., Schalling, M., Swanson, M. S., Thornton, C. A. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum. Molec. Genet. 10: 2165-2170, 2001. [PubMed: 11590133] [Full Text: https://doi.org/10.1093/hmg/10.19.2165]
Miller, J. W., Urbinati, C. R., Teng-umnuay, P., Stenberg, M. G., Byrne, B. J., Thornton, C. A., Swanson, M.S. Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 19: 4439-4448, 2000. [PubMed: 10970838] [Full Text: https://doi.org/10.1093/emboj/19.17.4439]