MBNL1

Muscleblind Like Splicing Regulator 1 (MBNL1) is an RNA splicing protein that in humans is encoded by the MBNL1 gene.[5][6][7] It has a well characterized role in Myotonic dystrophy where impaired splicing disrupts muscle development and function.[8] In addition to regulating mRNA maturation of hundreds of genes MBNL1 (along with its paralogs MBNL2 & MBNL3) autoregulate alternative splicing of the MBNL1 pre-mRNA transcript.[9] The founding member of the human MBNL family of proteins was the Drosophila Muscleblind protein (PMID: 9334280).

MBNL1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3D2N, 3D2Q, 3D2S
Identifiers
Aliases	MBNL1, EXP, EXP35, EXP40, EXP42, MBNL, muscleblind like splicing regulator 1
External IDs	OMIM: 606516 MGI: 1928482 HomoloGene: 23186 GeneCards: MBNL1
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q25.1-q25.2 Start 152,243,828 bp[1] End 152,465,780 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 D Start 60,472,830 bp[2] End 60,629,750 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • regulatory region RNA binding • double-stranded RNA binding • GO:0001948 protein binding • metal ion binding • RNA binding Cellular component • cytoplasm • centrosome • Stress granule • cell nucleus • nucleoplasm • cytosol Biological process • mRNA processing • regulation of RNA splicing • myoblast differentiation • in utero embryonic development • embryonic limb morphogenesis • RNA splicing • nervous system development • regulation of alternative mRNA splicing, via spliceosome Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4154	56758
Ensembl	ENSG00000152601	ENSMUSG00000027763
UniProt	Q9NR56 Q86VM6	Q9JKP5
RefSeq (mRNA)	NM_001314057 NM_021038 NM_207292 NM_207293 NM_207294 NM_207295 NM_207296 NM_207297 NM_001363870	NM_001253708 NM_001253709 NM_001253710 NM_001253711 NM_001253713 NM_020007 NM_001310514
RefSeq (protein)	NP_001300986 NP_066368 NP_997175 NP_997176 NP_997177 NP_997178 NP_997179 NP_997180 NP_001350799 NP_001363747 NP_001363748 NP_001363749 NP_001363750 NP_001363751 NP_001363752 NP_001363753 NP_001363754 NP_001363755 NP_001363756 NP_001363757 NP_001363758 NP_001363759 NP_001363760 NP_001363761 NP_001363762 NP_001363763 NP_001363764 NP_001363765 NP_001363766 NP_001363767 NP_001363768 NP_001363769 NP_001363770 NP_001363771 NP_001363772 NP_001363773 NP_001363774 NP_001363775 NP_001363776 NP_001363777 NP_001363778 NP_001363780 NP_001363782 NP_001300986.1 NP_997178.1 NP_997179.1 NP_997180.1	NP_001240637 NP_001240638 NP_001240639 NP_001240640 NP_001240642 NP_001297443 NP_064391
Location (UCSC)	Chr 3: 152.24 – 152.47 Mb	Chr 3: 60.47 – 60.63 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Human MBNL1 is an alternative splicing regulator that harbors dual function as both a repressor and activator for terminal muscle differentiation.[10] The repressive function of Human MBNL1 by sequestering at normal splice sites has been shown to lead to RNA-splicing defects that lead to muscular diseases.[11]

Human MBNL1 is a 370 amino acid protein[12]composed of four Zinc Finger protein domains of the CCCH type linked in tandem.[10] The MBNL1 protein specifically binds to double stranded CUG RNA expansions.[13] The Zinc Finger domains play a role in both protein:protein contacts as well as RNA:protein contacts when bound to an oligonucleotide.[10]

References

1. GRCh38: Ensembl release 89: ENSG00000152601 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027763 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, et al. (October 1997). "Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 4 (5): 307–13. doi:10.1093/dnares/4.5.307. PMID 9455477.
6. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (September 2000). "Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy". The EMBO Journal. 19 (17): 4439–48. doi:10.1093/emboj/19.17.4439. PMC 302046. PMID 10970838.
7. "Entrez Gene: MBNL1 muscleblind-like (Drosophila)".
8. Ho TH, Charlet-B N, Poulos MG, Singh G, Swanson MS, Cooper TA (August 2004). "Muscleblind proteins regulate alternative splicing". The EMBO Journal. 23 (15): 3103–12. doi:10.1038/sj.emboj.7600300. PMC 514918. PMID 15257297.
9. Konieczny P, Stepniak-Konieczna E, Sobczak K (January 2018). "MBNL expression in autoregulatory feedback loops". RNA Biology. 15 (1): 1–8. doi:10.1080/15476286.2017.1384119. PMC 5786016. PMID 28949831.
10. Teplova M, Patel DJ (December 2008). "Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1". Nature Structural & Molecular Biology. 15 (12): 1343–51. doi:10.1038/nsmb.1519. PMC 4689322. PMID 19043415.
11. Yadava RS, Kim YK, Mandal M, Mahadevan K, Gladman JT, Yu Q, Mahadevan MS (July 2019). "MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity". Human Molecular Genetics. 28 (14): 2330–2338. doi:10.1093/hmg/ddz065. PMC 6606845. PMID 30997488.
12. Tchaicheeyan O. Biophysical characterization of the 117 amino acids long N-terminal segment of D-Raf (Isoform A) (Thesis). Iowa State University. doi:10.31274/rtd-180813-16211.
13. "MBNL1 muscleblind like splicing regulator 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-05-05.

Further reading

• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Fardaei M, Larkin K, Brook JD, Hamshere MG (July 2001). "In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts". Nucleic Acids Research. 29 (13): 2766–71. doi:10.1093/nar/29.13.2766. PMC 55763. PMID 11433021.
• Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, et al. (September 2001). "Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2" (PDF). Human Molecular Genetics. 10 (19): 2165–70. doi:10.1093/hmg/10.19.2165. PMID 11590133.
• Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, Brook JD (April 2002). "Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells". Human Molecular Genetics. 11 (7): 805–14. doi:10.1093/hmg/11.7.805. PMID 11929853.
• Kino Y, Mori D, Oma Y, Takeshita Y, Sasagawa N, Ishiura S (March 2004). "Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats". Human Molecular Genetics. 13 (5): 495–507. CiteSeerX 10.1.1.598.7921. doi:10.1093/hmg/ddh056. PMID 14722159.
• Dansithong W, Paul S, Comai L, Reddy S (February 2005). "MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1". The Journal of Biological Chemistry. 280 (7): 5773–80. doi:10.1074/jbc.M410781200. PMID 15546872.
• Ho TH, Savkur RS, Poulos MG, Mancini MA, Swanson MS, Cooper TA (July 2005). "Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy". Journal of Cell Science. 118 (Pt 13): 2923–33. doi:10.1242/jcs.02404. PMID 15961406.
• Adereth Y, Dammai V, Kose N, Li R, Hsu T (December 2005). "RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1". Nature Cell Biology. 7 (12): 1240–7. doi:10.1038/ncb1335. PMC 2365307. PMID 16273094.
• Monferrer L, Artero R (2006). "An interspecific functional complementation test in Drosophila for introductory genetics laboratory courses". The Journal of Heredity. 97 (1): 67–73. doi:10.1093/jhered/esj003. PMID 16394256.
• Cardani R, Mancinelli E, Rotondo G, Sansone V, Meola G (2007). "Muscleblind-like protein 1 nuclear sequestration is a molecular pathology marker of DM1 and DM2". European Journal of Histochemistry. 50 (3): 177–82. PMID 16920640.
• Paul S, Dansithong W, Kim D, Rossi J, Webster NJ, Comai L, Reddy S (September 2006). "Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing". The EMBO Journal. 25 (18): 4271–83. CiteSeerX 10.1.1.673.6397. doi:10.1038/sj.emboj.7601296. PMC 1570429. PMID 16946708.
• Smith KP, Byron M, Johnson C, Xing Y, Lawrence JB (September 2007). "Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains". The Journal of Cell Biology. 178 (6): 951–64. doi:10.1083/jcb.200706048. PMC 2064620. PMID 17846170.