Stathmin-2 (STMN2) pre-mRNA cryptic splice and polyadenylation site (STMN2 cryptic site)

Stathmin-2 (STMN2) is a microtubule-destabilizing protein essential for axonal outgrowth and the maintenance of motor neuron connectivity (Klim et al., 2019, Nature Neuroscience). In neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear protein TDP-43 undergoes pathological mislocalization and depletion (Melamed et al., 2019, Nature Neuroscience). TDP-43 normally functions to suppress the recognition of a cryptic splice and polyadenylation site located within the first intron of the STMN2 pre-mRNA (Briese et al., 2019, Nature Communications). When TDP-43 levels are reduced in the nucleus, this cryptic site is utilized by the splicing machinery, leading to the inclusion of a cryptic exon and premature termination of the transcript. This results in a truncated mRNA that does not produce functional protein, leading to a loss of STMN2 and subsequent axonal degeneration (Theunissen et al., 2021, Frontiers in Aging Neuroscience). The STMN2 cryptic site has emerged as a high-priority therapeutic target, as restoring STMN2 levels may preserve motor function in ALS patients. Antisense oligonucleotides (ASOs) like QRL-201 and BIIB121 are designed to bind specifically to this cryptic site, preventing its recognition and allowing the production of full-length, functional STMN2 mRNA (QurAlis, 2023; Biogen, 2024).

Other names

STMN2 cryptic exonSTMN2 exon 2aSTMN2 cryptic polyadenylation siteSTMN2 cryptic splice site

Antisense oligonucleotide-mediated steric hindrance of cryptic splicing and polyadenylation to restore full-length mRNA expression.