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Intragenic Suppressors of McCune-Albright Syndrome Mutations

Award Number: R15DE020190
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: 03/17/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2014

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Intragenic Suppressors of McCune-Albright Syndrome Mutations - DESCRIPTION (provided by applicant): McCune-Albright Syndrome (MAS) is a genetic syndrome classically defined by the triad of fibrous dysplasia of the bone, precocious puberty, and cafi-au-lait skin hyperpigentation, often accompanied by other disorders of a hyperfunctioning endocrine system. A single amino acid substitution in the heterotrimeric G-protein subunit Gs causes constitutive activation of its signaling pathways, as the G-protein cannot hydrolyze GTP to inactivate itself. The long-term goal of this project is to contribute to the rational design of drugs to treat MAS patients by identifying sites on the mutated protein which can inactivate the MAS isoform of Gs. These suppressing sites can then be developed as targets for drugs that achieve a similar modification of the G-protein's activity. We have recently used a yeast system to identify an intragenic suppressor of a mutation in the yeast G-protein homologous to the MAS defect. The goal of the proposed experiments is to extend these preliminary results in the analysis of the suppressor and the identification of more suppressor alleles. The specific aims are: 1) Analyze intragenic suppressors using in vitro biochemical analysis of proteins expressed in and purified from E. coli. Assays will measure the GTPase activity of the Gs isoforms using a colorimetric assay for free phosphate, and measure their ability to adopt active vs. inactive conformations by observing differential trypsin digestion patterns and/or tryptophan autofluorescence. 2) Express suppressor alleles in mammalian cells, and analyze the cells for changes in basal and receptor-stimulated cAMP levels, along with changes in expression of cAMP-regulated genes using a reporter gene. 3) Identify more suppressor alleles by screening a library of random mutations in the constitutively active G-protein, and by performing further site-directed mutagenesis of the site identified in the first intragenic suppressor. Mapping these suppressor mutations to the structure of Gs will provide important foundational information for the design of more effective drugs for MAS patients. PUBLIC HEALTH RELEVANCE: McCune-Albright Syndrome patients exhibit bone weakness in the weight-bearing skeleton, malformations of the facial bones, abnormally early beginning of puberty, and patches of hyperpigmented skin. This syndrome is one of many diseases caused by the loss of normal regulation of G-proteins, cellular components that are essential for the responses to many hormones and neurotransmitters. This project aims to provide important basic science information that can be used in the rational design of drugs for McCune-Albright Syndrome and other disorders cause by G-protein defects.


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: 2014 ( Subtotal = $0 )
2014	2010	BENEDICTINE University	5700 COLLEGE RD	LISLE	IL	60532	DUPAGE	USA	Oral Diseases and Disorders Research	000	1	2/4/2014	NEW	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $223,472 )
2010	2010	BENEDICTINE University	5700 COLLEGE RD	LISLE	IL	60532	DUPAGE	USA	Oral Diseases and Disorders Research	001	1	7/29/2010	SUPPLEMENT FOR EXPANSION	$46,916
2010	2010	BENEDICTINE University	5700 COLLEGE RD	LISLE	IL	60532	DUPAGE	USA	Oral Diseases and Disorders Research	000	1	3/17/2010	NEW	$178,672
2010	2010	BENEDICTINE University	5700 COLLEGE RD	LISLE	IL	60532	DUPAGE	USA	Oral Diseases and Disorders Research	002	1	8/4/2010	SUPPLEMENT FOR EXPANSION	-$2,116
														Subtotal = $223,472

Grand Total All Awards = $223,472

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Intragenic Suppressors of McCune-Albright Syndrome Mutations

Award Number: R15DE020190

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: 03/17/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2014

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