Wednesday, July 2, 2025 7/2/2025

The role of continuous phenotypic variation in structural defects of the face

Award Number: R01DE019638
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/23/2010
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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The role of continuous phenotypic variation in structural defects of the face - Summary Despite tremendous progress in clinical genomics, nearly half of children with genetic disease never receive a diagnosis. One reason is that patients are initially diagnosed based on symptoms and physical manifestations but for many genetic conditions, those symptoms can vary dramatically even for patients with the same mutation. When patients with the same mutation have different phenotypes, that also has implications for treatment and prognosis, even when a molecular diagnosis is secured. The long-term goal of our research program is to understand how genotype is translated to variation in phenotype using a variety of model systems. In our previous funding cycle, we used an allelic series of Fibroblast growth factor 8 (Fgf8) mice and showed that levels of Fgf8 gene expression and downstream signalling factors were non-linearly related to the phenotype. Little change in phenotype occurs until Fgf8 drops below 50% compared to the wildtype, and then below that level small changes in Fgf8 produce large changes in the mean phenotype and its variance. The next step in our research advances this concept and helps generate a more mechanistic understanding of variable penetrance and robustness. Specifically, we propose two conceptually related aims that address distinct concepts in understanding the central question of how mutations perturb development to generate varied phenotypic outcomes. In specific Aim 1, we test mechanisms by which gene interactions within a pathway generate variable penetrance and expressivity. Our previous research has identified epistatic interactions that may modulate FGF8, and in this Aim, we test these interactions directly. In Specific Aim 2, we test how a mutation that affects a specific but ubiquitous process generates a multi-modal range of phenotypes. This is important because genetic diseases often involve disruptions to mechanisms that operate across diverse tissues and at many points in development and yet result in highly specific birth defects such as holoprosencephaly or cleft lip and palate. As a model for this general phenomenon, we investigate the effects of a null mutation in Nitric Oxide Synthase Interacting Protein (Nosip) in mice. NOSIP is an E3-monoubiquitin ligase that modifies activity of target proteins with diverse developmental roles. In both aims, we employ a highly innovative combination of imaging, morphometric, transcriptomic and experimental approaches to integrate multiple levels of input (genetic, molecular, cellular) to understand how the effects of a mutation cascade across levels from gene expression to cellular dynamics to influence organismal form.


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 = $571,616 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	14	11/22/2024	NON-COMPETING CONTINUATION	$514,454
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	14	5/5/2025	NON-COMPETING CONTINUATION	$57,162
														Subtotal = $571,616

Issue Date FY: 2024 ( Subtotal = $560,183 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	13	6/19/2024	NON-COMPETING CONTINUATION	$45,729
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	13	11/6/2023	NON-COMPETING CONTINUATION	$514,454
														Subtotal = $560,183

Issue Date FY: 2023 ( Subtotal = $575,474 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	12	11/30/2022	NON-COMPETING CONTINUATION	$517,927
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	003	12	2/9/2023	NON-COMPETING CONTINUATION	$57,547
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	11	11/10/2022	COMPETING CONTINUATION	$22,281
2023	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	10	11/10/2022	NON-COMPETING CONTINUATION	-$22,281
														Subtotal = $575,474

Issue Date FY: 2022 ( Subtotal = $601,777 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	11	12/1/2021	COMPETING CONTINUATION	$601,777
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	10	11/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $601,777

Issue Date FY: 2020 ( Subtotal = $538,154 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	10	2/14/2020	NON-COMPETING CONTINUATION	$53,830
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	10	1/22/2020	NON-COMPETING CONTINUATION	$484,475
2020	2014	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	10/1/2019	NON-COMPETING CONTINUATION	-$151
														Subtotal = $538,154

Issue Date FY: 2019 ( Subtotal = $538,365 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	9	12/10/2018	NON-COMPETING CONTINUATION	$538,365
														Subtotal = $538,365

Issue Date FY: 2018 ( Subtotal = $538,423 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	8	12/1/2017	NON-COMPETING CONTINUATION	$484,582
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	8	4/19/2018	NON-COMPETING CONTINUATION	$53,841
														Subtotal = $538,423

Issue Date FY: 2017 ( Subtotal = $572,686 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	7	11/29/2016	NON-COMPETING CONTINUATION	$515,417
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	7	5/26/2017	NON-COMPETING CONTINUATION	$57,269
														Subtotal = $572,686

Issue Date FY: 2016 ( Subtotal = $631,243 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	6	6/24/2016	COMPETING CONTINUATION	$14,597
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	6	12/28/2015	COMPETING CONTINUATION	$616,646
2016	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	12/21/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $631,243

Issue Date FY: 2014 ( Subtotal = $330,468 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	5	3/4/2014	NON-COMPETING CONTINUATION	$33,047
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	2/24/2014	NON-COMPETING CONTINUATION	$297,421
														Subtotal = $330,468

Issue Date FY: 2013 ( Subtotal = $317,249 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	4	2/28/2013	NON-COMPETING CONTINUATION	$297,421
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	4	5/10/2013	NON-COMPETING CONTINUATION	$19,828
														Subtotal = $317,249

Issue Date FY: 2012 ( Subtotal = $330,468 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	2/8/2012	NON-COMPETING CONTINUATION	$330,468
														Subtotal = $330,468

Issue Date FY: 2011 ( Subtotal = $323,792 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	2/16/2011	NON-COMPETING CONTINUATION	$300,426
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	2	5/27/2011	NON-COMPETING CONTINUATION	$23,366
														Subtotal = $323,792

Issue Date FY: 2010 ( Subtotal = $347,431 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	7/23/2010	NEW	$347,431
														Subtotal = $347,431

Grand Total All Awards = $6,777,329

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The role of continuous phenotypic variation in structural defects of the face

Award Number: R01DE019638

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/23/2010

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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