The major goal of this project is to discover genetic factors and biophysical mechanisms that cause congenital contractures (e.g., clubfoot) in Distal Arthrogryposis (DA) syndromes, the most common cause of heritable contractures. We have delineated 10 different DA syndromes (i.e., DA1-DA10) and discovered that mutations in any one of 9 genes that encode myosins or regulatory proteins (i.e., troponin complex, tropomyosins, myosin binding proteins) collectively explain ~50% of DA cases. Using a resource of ~340 families and nearly 600 cases with DA, we will in Aim 1 discover new genes for both well known and novel forms of DA. This will be accomplished using both conventional candidate gene and linkage approaches, and facilitated by mapping data that show we have defined several new DA loci. We will also use a novel strategy to find genes for rare, monogenic disorders that involves massively parallel resequencing of all protein coding sequences in the human genome (the """"""""exome""""""""). The proteins encoded by the genes we have, to date, found to underlie DA are perhaps both quantitatively and qualitatively the most important molecules in skeletal muscle as they bring about the production of force. Consistent with this observation, we have shown that individual myofibers from persons with mutations in MYH3, the most common cause of DA, exhibit both diminished force production and increased time to relaxation. Therefore, in Aim 2 we will explore the mechanism(s) by which dysfunction of the contractile apparatus of skeletal myofibers in persons with mutations in different DA genes cause congenital contractures. Discovery of the genetic variants influencing DA disorders will substantially expand our understanding of biology of congenital contractures and will facilitate accurate diagnosis and improved management of myopathies in general, a group of diseases that broadly affects children and adults in our country. Our findings may well provide insights for novel therapeutics to mitigate or prevent congenital contractures in the U.S. and globally.)

Public Health Relevance

The major goal of this project is to identify gene variations that cause congenital contractures and understand how these variations affect force production in muscle. This goal will be accomplished by applying both conventional and novel gene discovery approaches using a cohort of 339 families with distal arthrogryposis syndromes, and directly measuring the contractile performance of skeletal myofibers from affected persons. Finding these genes will improve our understanding of the biology of congenital contractures, improve their management, and provide information for the development of novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD048895-09
Application #
8687497
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Javois, Lorette Claire
Project Start
2005-02-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cheng, Yuanhua; Regnier, Michael (2016) Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility. Arch Biochem Biophys 601:11-21
Racca, Alice W; Klaiman, Jordan M; Pioner, J Manuel et al. (2016) Contractile properties of developing human fetal cardiac muscle. J Physiol 594:437-52
Pioner, Josè Manuel; Racca, Alice W; Klaiman, Jordan M et al. (2016) Isolation and Mechanical Measurements of Myofibrils from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Stem Cell Reports 6:885-96
Chong, Jessica X; Yu, Joon-Ho; Lorentzen, Peter et al. (2016) Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet Med 18:788-95
Lehman, William; Medlock, Greg; Li, Xiaochuan Edward et al. (2015) Phosphorylation of Ser283 enhances the stiffness of the tropomyosin head-to-tail overlap domain. Arch Biochem Biophys 571:10-5
Racca, Alice W; Beck, Anita E; McMillin, Margaret J et al. (2015) The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle. Hum Mol Genet 24:3348-58
Chong, Jessica X; Burrage, Lindsay C; Beck, Anita E et al. (2015) Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Am J Hum Genet 96:841-9
Chong, Jessica X; McMillin, Margaret J; Shively, Kathryn M et al. (2015) De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet 96:462-73
Beck, Anita E; McMillin, Margaret J; Gildersleeve, Heidi I S et al. (2014) Genotype-phenotype relationships in Freeman-Sheldon syndrome. Am J Med Genet A 164A:2808-13
McMillin, Margaret J; Beck, Anita E; Chong, Jessica X et al. (2014) Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet 94:734-44

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