Pathogenic DDX39A Variant Disrupts Nuclear Homeostasis and Causes an Early-Onset Neurodegenerative Disorder With Cerebral Atrophy.

Abstract

Neurodevelopmental disorders arising from mutations in RNA-processing factors are increasingly recognized but remain mechanistically underexplored. Here, we identify that variant (c.485A>C; p.Lys137Gln) in DDX39A in a 7-month-old proband presenting with global developmental delay, microcephaly, seizures, hypotonia, and brain atrophy with corpus callosum thinning. DDX39A encodes a DEAD-box RNA helicase essential for mRNA splicing and export via the TREX complex. Functional studies in proband-derived fibroblasts revealed that while transcript and protein levels of DDX39A-K137Q were unaffected, the mutant protein displayed aberrant nuclear clumping and failed to interact with the TREX component THOC1. Structural modeling demonstrated that Lys137 mediates critical inter- and intra-molecular interactions, which are disrupted by the K137Q substitution. This loss destabilizes the DDX39A-THOC1 interface, impairing TREX complex integrity. The mutant cells exhibited severe nuclear morphological abnormalities, disrupted nuclear lamina organization, and increased cell death. Transcriptomic network analysis and gene ontology revealed enrichment of DDX39A interactions in mRNA export, splicing, and nucleocytoplasmic transport-functions essential for neuronal development. Temporal and regional brain expression data showed that DDX39A is highly expressed during early postnatal life and across multiple brain regions, indicating its importance in early brain maturation. Our findings establish DDX39A-K137Q as a pathogenic variant that impairs nuclear RNA processing and structural homeostasis, leading to a severe neurodegenerative phenotype. This study identifies the role of RNA helicases in neurodevelopment and explores DDX39A as a novel gene implicated in pediatric neurodegenerative disease.