Insulin receptor (INSR) pre-mRNA CUG-binding protein 1 (CUG-BP1) splice-regulatory site (INSR exon 11 SRS)

The Insulin receptor (INSR) pre-mRNA CUG-BP1 splice-regulatory site is a critical cis-acting RNA element located within the INSR transcript that governs the alternative splicing of exon 11 (Savkur et al., 2001, Nature Genetics). This site is primarily regulated by the antagonistic binding of CUG-binding protein 1 (CUG-BP1/CELF1) and Muscleblind-like 1 (MBNL1); CELF1 promotes the exclusion of exon 11 to produce the IR-A isoform, while MBNL1 promotes its inclusion to produce the IR-B isoform (Kuyumcu-Martinez et al., 2007, Molecular Cell). IR-B is the predominant isoform in adult metabolic tissues and possesses high affinity for insulin, whereas IR-A is a fetal isoform with lower metabolic signaling efficiency. In Myotonic Dystrophy Type 1 (DM1), the expansion of CUG repeats leads to the sequestration of MBNL1 and the stabilization of CELF1, resulting in an abnormal shift toward IR-A and subsequent insulin resistance (Paul et al., 2006, Journal of Biological Chemistry). Therapeutic strategies targeting this regulatory region, such as splice-switching antisense oligonucleotides (ASOs), aim to restore the balance of INSR isoforms by blocking CELF1 binding or promoting exon 11 inclusion (Wheeler et al., 2012, Nature). This target is a key focus for addressing the metabolic dysfunction associated with RNA-dominant neuromuscular disorders.

Other names

INSR exon 11 splice-regulatory elementCELF1 binding site on INSR pre-mRNAInsulin receptor exon 10-12 splice regionINSR pre-mRNA exon 11

Modulation of alternative splicing to promote the inclusion of exon 11 in the insulin receptor (INSR) mRNA, thereby increasing the expression of the IR-B isoform.