Immunoglobulin mu-binding protein 2 (IGHMBP2) pre-mRNA cryptic splice site variant (IGHMBP2 cryptic splice site)

Immunoglobulin mu-binding protein 2 (IGHMBP2) is a DNA/RNA helicase essential for motor neuron survival and RNA processing (UniProt P38935). Mutations in the IGHMBP2 gene, such as those creating or activating cryptic splice sites in the pre-mRNA, lead to aberrant splicing and a deficiency of functional protein (Groen et al., 2018, PMID: 29133313). This deficiency causes severe neuromuscular diseases, including Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) and Charcot-Marie-Tooth disease type 2S (CMT2S). The IGHMBP2 pre-mRNA cryptic splice site variant is a target for antisense oligonucleotides (ASOs) that aim to restore correct splicing by sterically blocking the aberrant site (Kaczmarek et al., 2021, PMID: 33616314). By redirecting the splicing machinery, these ASOs facilitate the production of full-length, functional IGHMBP2 mRNA and protein (Saladini et al., 2020, PMID: 32051246). This therapeutic approach is designed to address the root genetic cause of the disease and prevent progressive muscle weakness and respiratory failure. Current research is focused on the safety and efficacy of these ASOs in preclinical models and their potential transition to clinical trials. The specificity of ASOs for the cryptic splice site minimizes impact on the normal splicing of other genes, though off-target effects remain a consideration.

Other names

IGHMBP2 pseudoexonIGHMBP2 aberrant splice siteIGHMBP2 intronic splice variantIGHMBP2 c.1235+651G>A variantIGHMBP2 pseudoexon inclusion

Splice modulation via steric hindrance of cryptic splice sites to restore functional mRNA and protein expression.