Tuesday, July 1, 2025 7/1/2025

Cellular and molecular mechanisms underlying DDX3X syndrome

Award Number: R01NS120667
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Cellular and molecular mechanisms underlying DDX3X syndrome - Abstract Mutations in DDX3X are strongly associated with autism spectrum disorder (ASD), and may account for 1-3% of unexplained developmental delay (DD) in females, making this one of the most common of neurodevelopmental disorders. DDX3X is considered a high confidence ASD gene by SFARI gene. DDX3X encodes an RNA-binding protein of the DEAD-box helicase family. While broadly implicated in mRNA metabolism, DDX3X is best characterized as a translational regulator. Despite the robust link between DDX3X and ASD, virtually nothing is known about DDX3X function in the developing brain nor the mechanisms by which DDX3X mutations perturb cellular function. Further, it remains largely unknown how DDX3X impacts neural progenitors and how it controls translation of its targets. This limits our understanding of the causes of ASD for this common condition and the potential for therapeutic intervention. Our proposal addresses these gaps by investigating how DDX3X mutations impair brain development and protein synthesis. Our preliminary data indicates requirements for DDX3X in neural progenitors and suggests that translational regulation may be relevant for disease. This has led to our central hypothesis that DDX3X mutations impair neurogenesis by disrupting the progenitor cell cycle and translation of key targets. To address this hypothesis we will: Define how DDX3X loss of function impairs cell fate specification in mouse models, determine how DDX3X missense mutations impair human neural progenitor function and differentiation, and identify the mechanism(s) by which genetic variants in DDX3X alter protein synthesis. Our diverse scientific approaches enable this multifaceted understanding of DDX3X function and developmental role. Upon completion of this study we will gain fundamental insights into DDX3X biology and guide a framework for therapeutic intervention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $590,756 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/16/2024	NON-COMPETING CONTINUATION	$590,756
														Subtotal = $590,756

Issue Date FY: 2024 ( Subtotal = $636,703 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/11/2023	NON-COMPETING CONTINUATION	$590,756
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	7/12/2024	NON-COMPETING CONTINUATION	$0
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/16/2024	NON-COMPETING CONTINUATION	$45,947
														Subtotal = $636,703

Issue Date FY: 2023 ( Subtotal = $716,883 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	8/10/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/7/2022	NON-COMPETING CONTINUATION	$590,756
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/2/2023	NON-COMPETING CONTINUATION	$65,638
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	6/15/2023	SUPPLEMENT FOR EXPANSION	$31,260
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	8/17/2023	SUPPLEMENT FOR EXPANSION	$29,229
														Subtotal = $716,883

Issue Date FY: 2022 ( Subtotal = $662,807 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/28/2022	NON-COMPETING CONTINUATION	$66,280
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/9/2021	NON-COMPETING CONTINUATION	$596,527
														Subtotal = $662,807

Issue Date FY: 2021 ( Subtotal = $678,057 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/21/2020	NEW	$678,057
														Subtotal = $678,057

Grand Total All Awards = $3,285,206

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Cellular and molecular mechanisms underlying DDX3X syndrome

Award Number: R01NS120667

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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