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Genomic and functional characterization of ASD and ID-associated MYT1L mutation

Award Number: R01MH124808
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Genomic and functional characterization of ASD and ID-associated MYT1L mutation - Recent advances in human genetics have defined hundreds of causal variants for Autism Spectrum Disorder (ASD) and other intellectual and developmental disabilities (IDDs). However, substantial effort is required to define downstream disease processes and thus to guide development of interventions for each one. One such new ASD gene is MYT1L – while mutations in MYT1L have recently become associated with ASD and Intellectual Disability (IDD) in humans, the role of MYT1L in neural cells and circuits is unclear. Thus, here, we propose a comprehensive mechanistic investigation of MYT1L. This project uses both cutting-edge established workflows as well as innovative new approaches to enable in-depth study of MYT1L loss at the molecular, cellular, structural, and behavioral circuit levels. We will utilize two complementary experimental systems, mouse models and human induced pluripotent stem cell (iPSC)-derived neurons, to define MYT1L's normal roles, and to identify the consequences and reversibility of MYT1L loss. We focus initially on a mutation identified in a patient with a MYT1L putative loss-of-function variant who has ASD and ID. In addition to knock-in of this variant into isogenic control PSC lines, we derived iPSC models from this subject, with and without MYT1L variant correction, enabling us to define consistent consequences of MYT1L mutation across human genetic backgrounds. We also developed mouse models targeting the paralogous amino acid, to enable studies of the consequence of MYT1L loss on brain structure, physiology, and behavioral circuit function. Further, cutting-edge gene therapy-like tools developed for both mouse and human models will allow us to investigate the effects of rescuing gene function. Similar landmark experiments profoundly changed the understanding of other neurodevelopmental disorders by demonstrating that a substantial proportion of the phenotype was reversible, thus spurring the development of therapeutics based on rescuing gene expression. Together, the experiments performed here will elucidate the requirements for and mechanisms by which MYT1L controls brain development and function, will determine how these are disrupted by pathogenic MYT1L mutation, and could also chart a course towards MYT1L-targeted therapies.


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 = $648,168 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	5	11/29/2024	NON-COMPETING CONTINUATION	$648,168
														Subtotal = $648,168

Issue Date FY: 2024 ( Subtotal = $762,550 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	000	4	11/1/2023	NON-COMPETING CONTINUATION	$686,295
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	001	4	6/27/2024	NON-COMPETING CONTINUATION	$76,255
														Subtotal = $762,550

Issue Date FY: 2023 ( Subtotal = $698,530 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	3	11/8/2022	NON-COMPETING CONTINUATION	$628,677
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	3	1/23/2023	NON-COMPETING CONTINUATION	$69,853
														Subtotal = $698,530

Issue Date FY: 2022 ( Subtotal = $737,340 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$73,733
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	2	10/22/2021	NON-COMPETING CONTINUATION	$663,607
														Subtotal = $737,340

Issue Date FY: 2021 ( Subtotal = $786,372 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	1	5/4/2021	NEW	$78,636
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	1	11/18/2020	NEW	$707,736
														Subtotal = $786,372

Grand Total All Awards = $3,632,960

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Genomic and functional characterization of ASD and ID-associated MYT1L mutation

Award Number: R01MH124808

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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