Iron-sulfur cluster assembly enzyme mRNA (ISCU mRNA)

Iron-sulfur cluster assembly enzyme (ISCU) mRNA encodes a vital scaffold protein required for the synthesis of iron-sulfur [Fe-S] clusters, which serve as essential inorganic cofactors for enzymes involved in the mitochondrial respiratory chain and various metabolic pathways (UniProt Q9H1K1). This mRNA is a primary therapeutic target for ISCU myopathy, also known as hereditary myopathy with lactic acidosis (HMLA), a condition caused by a deep intronic mutation (c.418+382G>C) that induces aberrant splicing and the inclusion of a 100-bp pseudoexon (Jansson et al., 2009). The resulting truncated protein leads to severe mitochondrial dysfunction and exercise intolerance. Therapeutic interventions focus on using splice-switching antisense oligonucleotides (ASOs) to mask the cryptic splice site, thereby restoring normal mRNA processing and functional protein levels (Wikström et al., 2019). Additionally, ISCU mRNA is a known target of microRNA-210 (miR-210), which downregulates its expression under hypoxic conditions, contributing to the metabolic shift seen in pulmonary arterial hypertension and solid tumors (Chan et al., 2009). Targeting the ISCU mRNA or its regulatory microRNAs represents a promising strategy for treating both rare genetic disorders and more common metabolic and vascular diseases.

Other names

Iron-sulfur cluster scaffold protein mRNANifU-like protein mRNAHMLA mRNAISCU1 mRNAISCU2 mRNA

Splice-switching oligonucleotides bind to the pre-mRNA to block cryptic splice sites, preventing the inclusion of a deleterious pseudoexon and restoring the production of full-length, functional ISCU protein.