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Insights into EHMT1 Variants in the Neurodevelopmental Disorder Kleefstra Syndrome through Structural Dynamics and Functional Analysis

Award Number: R21HD116120
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Insights into EHMT1 Variants in the Neurodevelopmental Disorder Kleefstra Syndrome through Structural Dynamics and Functional Analysis - Euchromatic histone methyltransferase 1 (EHMT1, also known as GLP) is a key histone methylation writer intricately associated with Kleefstra Syndrome (KS), a multifaceted neurodevelopmental disorder characterized by intellectual disability, developmental delay, childhood hypotonia, distinctive facial features, and comorbidities, including autism spectrum disorders. Its modular structure encompasses the ankyrin repeat scaffolding domain responsible for methyl-lysine recognition (histone reader function) and the SET catalytic domain governing histone methylation (writer function). Despite the identification of numerous mutations in patients, their precise effects on EHMT1 function and direct links to pathogenicity remain elusive. As such, most are annotated as variants of uncertain significance (VUS). To enhance EHMT1 genomic variation interpretation and uncover novel insights into its structure-function relationship, we have harnessed a comprehensive computational approach to perform deep variant phenotyping, which integrates mechanisms rooted in sequence, structure, and dynamics. Through this approach, we have identified domain-specific metrics and reclassified KS variants within the SET domain. In this proposal, we aim to perform the first in-depth comprehensive deep variant phenotyping of KS-associated variants within the ankyrin repeat domain and further elucidate the structure- function relationship of variants within both the SET and ankyrin repeat domains to better understand pathophysiological mechanisms underlying the disease. Our CENTRAL HYPOTHESIS is that KS-associated genomic variants within EHMT1 alter structural dynamics as well as biochemical and biophysical properties to impact domain-specific functions. The rationale is that comprehensive investigations into the biochemical, biophysical, and structural dynamics of KS-associated genomic variants within the EHMT1 SET and ankyrin domains will reveal detailed mechanisms underlying the disruption of domain-specific functions, providing novel insight into the molecular basis of KS. To test our central hypothesis, we propose two interrelated, yet independent AIMS: (1) to define the impact of KS-associated genomic variants within the ankyrin domain on the structural dynamics of EHMT1 using deep variant phenotyping and (2) to elucidate the underlying biochemical and biophysical mechanisms of EHMT1 dysfunction caused by KS-associated genomic variants. These findings will establish crucial foundations for subsequent investigations involving cell-based and animal model studies. Ultimately, our discoveries will have the potential to guide future therapeutic strategies aimed at ameliorating the impacts of KS-associated variants on EHMT1 function and, by extension, on chromatin regulation and epigenetic processes. Collectively, these studies will enhance the annotation of genomic variants and facilitate the development of more precise, personalized approaches to disease management and treatment, ultimately improving the well-being of affected children and offering support to their families.


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: 2027 ( Subtotal = $194,527 )
2027	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Child Health and Human Development Extramural Research	000	1	10/15/2026	NEW	-$196,635
2027	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Child Health and Human Development Extramural Research	002	1	10/27/2026	NEW	$196,635
2027	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Child Health and Human Development Extramural Research	003	1	10/27/2026	NEW	$0
2027	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Child Health and Human Development Extramural Research	001	2	10/23/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$194,527
														Subtotal = $194,527

Issue Date FY: 2026 ( Subtotal = -$197,059 )
2026	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Child Health and Human Development Extramural Research	000	1	9/29/2026	NEW	-$197,059
														Subtotal = -$197,059

Issue Date FY: 2024 ( Subtotal = $429,000 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Child Health and Human Development Extramural Research	000	1	9/11/2024	NEW	$429,000
														Subtotal = $429,000

Grand Total All Awards = $426,468

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Insights into EHMT1 Variants in the Neurodevelopmental Disorder Kleefstra Syndrome through Structural Dynamics and Functional Analysis

Award Number: R21HD116120

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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