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Impaired cortical development and translational control in a missense mouse model of DDX3X syndrome

ABSTRACT: Heterozygous mutations in the X-linked RNA helicase DDX3X cause DDX3X syndrome, a rare neurodevelopmental disorder associated with cortical malformation and autism. Amongst the ~200 known de novo DDX3X variants, half are missense while the others are predicted loss-of-function (LoF). LoF mouse models reveal DDX3X loss impairs progenitors’ ability to generate excitatory neurons. Yet, how missense mutations impact corticogenesis in vivo is unknown. Here, we generated a conditional mouse model of Ddx3xT532M, a clinically severe and recurrent DDX3X syndrome mutation found in females. Using Cre-mediated expression of Ddx3xT532M in cortical progenitors and their progeny, we show this mutation alters corticogenesis and translation. Ddx3xT532M conditional knock-in (KI) males have severe microcephaly and apoptosis. In contrast, Ddx3xT532M conditional heterozygous (cHet) females exhibit only mild reductions in cortical size and neurogenesis. Using polysome fractionation of Ddx3xT532M and Ddx3xLoF cHet female cortices, we discover that Ddx3xT532M affects translation of key targets, with qualitative differences from Ddx3xLoF cHet females. Collectively, these cellular and molecular findings suggest that, the clinically severe Ddx3xT532M variant in cHet females is phenotypically similar to, but molecularly distinct from, Ddx3x haploinsufficiency in corticogenesis. Our study establishes a new model for understanding how missense mutations may cause DDX3X syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE296911 | GEO | 2025/11/17

REPOSITORIES: GEO

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