PRUNE1 encodes a phosphodiesterase enzyme that preferentially hydrolyzes cAMP over cGMP and functions as a critical regulator of cellular processes including proliferation, migration, and neurogenesis 1. The protein contains a DHH (aspartic acid-histidine-histidine) phosphodiesterase domain essential for its enzymatic activity and acts as a negative regulator of NME1/NME2 tumor metastasis suppressors through direct protein interactions 1. PRUNE1 plays important roles in microtubule polymerization regulation and neurogenesis 2. Loss-of-function mutations in PRUNE1 cause neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA), characterized by developmental delay, intellectual disability, and structural brain abnormalities including corpus callosum thinning and cerebellar atrophy 324. The clinical spectrum is variable, with some patients lacking typical microcephaly 24. In cancer contexts, PRUNE1 promotes multiple myeloma progression by enhancing purine metabolism and mitochondrial function 5, and is epigenetically regulated by PAD2-mediated histone citrullination in pancreatic cancer, where it modulates the tumor microenvironment 6. These findings establish PRUNE1 as both a neurodevelopmental disease gene and oncogenic factor.