Immunoglobulin mu-binding protein 2 (IGHMBP2) pre-mRNA cryptic splice site variant c.1235+894C>A (IGHMBP2 c.1235+894C>A)

The IGHMBP2 cryptic splice site variant c.1235+894C>A is a deep intronic mutation located within intron 8 of the Immunoglobulin mu-binding protein 2 (IGHMBP2) gene (Saladini et al., 2022). This mutation creates a de novo 5' donor splice site, which leads to the inclusion of a 65-base pair pseudoexon into the mature mRNA transcript, causing a frameshift and a premature termination codon (Nizzardo et al., 2015). The resulting loss of functional IGHMBP2 protein, an ATP-dependent helicase involved in DNA replication and RNA processing, leads to Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1), a severe autosomal recessive motor neuron disease (Corti et al., 2012). This cryptic splice site serves as a therapeutic target for splice-switching antisense oligonucleotides (ASOs) designed to sterically block the recognition of the mutation by the spliceosome, thereby restoring normal splicing (Saladini et al., 2022). By preventing pseudoexon inclusion, these ASOs aim to increase the production of full-length, functional IGHMBP2 protein and alleviate the disease phenotype. Experimental studies in mouse models have demonstrated that targeting this specific variant can improve motor function and extend survival (Saladini et al., 2022).

Other names

c.1235+894C>AIGHMBP2 deep intronic mutationSMARD1-associated cryptic splice siteIGHMBP2 pseudoexon variant

Splice-switching to mask cryptic splice sites and restore canonical mRNA processing