Characterization of a Novel Mouse Model of DDX3X Syndrome, a Recently Identified Neurodevelopmental Disorder

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
A. Boitnott1,2,3, D. Ung1,2,3, D. Mendonca1,2,3, K. Niblo1,2, E. Drapeau1,2 and S. De Rubeis1,2,3, (1)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, (2)Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, (3)Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY

DDX3X syndrome, first described in 2015, is a rare genetic neurodevelopmental disorder that accounts for up to 2% of unexplained intellectual disability (ID) in females, attributable to de novo mutations in DEAD box helicase 3, X-linked (Ddx3x). However, there have been a few reported cases of males with DDX3X syndrome, where a pathogenic Ddx3x mutation is inherited from an unaffected mother. The neurobiology of Ddx3x underlying this sex specificity is unexplored, leaving pharmacological treatment for this disorder currently intangible. Individuals diagnosed with DDX3X syndrome are characterized by developmental delay/ID, neurological anomalies, motor impairments, and atypical behavior, such as Autism Spectrum Disorder (ASD). Despite clinical classification, there are no mouse models characterized for DDX3X syndrome.


We aim to assess the effect of DDX3X deficiency on neurodevelopment and behavior, while establishing a pre-clinical mouse model for DDX3X syndrome. The animal model will be essential in advancing knowledge regarding this disorder, revealing critical data that may advise successful treatment plans for DDX3X syndrome and, more broadly, ID and ASD.


We have generated a mouse line with construct validity for DDX3X syndrome, where Ddx3x is ablated only in embryonic tissues using a Sox-Cre driver line. Neurodevelopment and behavior of these mice is assessed by a battery of physical, sensory, and motor milestone tasks between postnatal days 1-21. Innate anxiety, motor coordination, memory, sociability, and fear conditioning is assessed on adult mice to characterize cognitive and behavioral abnormalities. During postnatal development, brain morphology and microanatomy is assessed using Nissl staining and mouse MRI brain imaging.


We have found that Ddx3x ablation in males is lethal, as no Ddx3x null male mice (Ddx3x-/y) are born. Also, female mice heterozygous for Ddx3x (Ddx3x+/-)­ are born less frequently. We show that Ddx3x+/- females have reduced protein expression in total cortex and cortical synapses. Behavior and development assessments show that Ddx3x+/- mice have various delayed developmental milestones—physical, such as reduced weight; sensory, such as delayed auditory startle response; and motor, such as delayed surface righting—as well as motor impairments, such as gait anomalies. These results are consistent with clinical features observed in DDX3X syndrome, supporting face validity of the mouse model. Additionally, we have found no gross differences in brain morphology between adult Ddx3x+/- and control mice and are investigating morphology during earlier development.


We have generated a mouse model with construct validity for DDX3X syndrome and initial evidence, from observations of developmental delay, for face validity. This model is useful to understand the mechanisms underlying DDX3X syndrome and develop future therapies for DDX3X syndrome that might be applicable to the broader ID and ASD populations.

See more of: Animal Models
See more of: Animal Models