GPKOW is an X-linked nuclear RNA-binding protein essential for pre-mRNA splicing as a core spliceosomal component 1. The protein contains G-patch and KOW domains that facilitate interactions with the DEAH-box helicase DHX16/hPRP2 and direct RNA binding 2. GPKOW is critical for spliceosomal assembly and function; its immunodepletion from nuclear extracts abolishes splicing activity, which is restored by recombinant GPKOW addition 2. The protein cooperates with DHX16 through ordered spliceosomal protein interactions, particularly during early splicing catalysis 3. Loss-of-function GPKOW variants cause a severe multisystemic X-linked disorder characterized by intrauterine growth restriction, microcephaly, and abnormalities affecting the eyes, brain, skin, and skeleton 4. C-terminal frameshift variants produce truncated proteins with reduced stability and partial loss-of-function activity that exhibits dosage sensitivity 4. Splice site variants similarly reduce wild-type GPKOW mRNA and protein levels, creating a male-lethal perinatal phenotype 1. Additionally, GPKOW functions as an influenza A virus host factor, showing significant protein turnover changes during viral infection 5. These findings establish GPKOW as essential for normal fetal development and spliceosomal function.