Project 1 will seek to identify genetic modifiers of Facioscapulohumeral muscular dystrophy by focusing on nonmanifesting earners of the 4qA allele. Several carriers of the 4q161PAS allele have been identified in Italy who have no manifestations nor family history of the disease. In addition, our Wellstone Center has identified families containing affected and nonmanifesting relatives who share the same allele and similarly express DUX4-FL in skeletal muscle. These individuals suggest that the current genetic signature of FSHD (D4Z4 contraction in the presence of the 4qA allele and a polyadenylation sequence in a distal pLAM sequence) is not an exclusive determinant of FSHD and that there is either a """"""""second-hit"""""""" resulting in disease or a protective gene resulting in muscle health. Project 1 has two broad aims.
The first aim i s to identify and characterize nonmanifesting carriers of the FSHD allele. 10 nonmanifesting carriers without family history have been identified and examined in Italy and 4 nonmanifesting carriers from FSHD families have been identified and examined in the U.S. to date. Additional subjects will be recruited from the FSH Society and a large epidemiological study by the Italian National Registry for FSHD. Subjects will have detailed genotypic and phenotypic characterization including determination of DUX4-fl expression, muscle strength, muscle histopathology and muscle imaging.
The second aim will identify genetic modifiers of FSHD through the use of whole-exome sequencing of nonmanifesting and affected individuals. In addition to an unbiased analysis of all -20,000 human genes, we will also test targeted hypotheses regarding whether variants in any of the ~300 known muscle-disease related genes are associated with FSHD manifestion, singly or collectively. Project 1 will interact closely with Project 2 where RNAseq will generate RNA sequence information that will confirm and add to the exome sequence data to identify genetic changes related to modifiers. Project 1 will also identify subjects that will be the source of donation of muscle and myoblasts for xenografts in Project 3. Finally, Project 1 will be assisted by the Cell Core which will provide histopathological analysis and CD56 myoblasts FACS sorted from muscle biopsy specimens.

Public Health Relevance

The occurrence of nonmanifesting carriers of a permissive FSHD allele suggests that there are important modifiers to the development of weakness. This project will identify, characterize and sequence the exome of these individuals with the goal of identifying genetic modifiers. Modifiers of disease will be excellent future therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54HD060848-07
Application #
8621139
Study Section
Special Emphasis Panel (ZNS1-SRB-S (57))
Project Start
Project End
Budget Start
2013-09-16
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$284,764
Indirect Cost
$53,047
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Sakellariou, Paraskevi; O'Neill, Andrea; Mueller, Amber L et al. (2016) Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts. Skelet Muscle 6:4
Chen, Jennifer Cj; King, Oliver D; Zhang, Yuanfan et al. (2016) Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther 24:1405-11
Henninger, Nils; Bouley, James; Sikoglu, Elif M et al. (2016) Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1. Brain 139:1094-105
Jones, Takako I; King, Oliver D; Himeda, Charis L et al. (2015) Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin Epigenetics 7:37
Homma, Sachiko; Beermann, Mary Lou; Boyce, Frederick M et al. (2015) Expression of FSHD-related DUX4-FL alters proteostasis and induces TDP-43 aggregation. Ann Clin Transl Neurol 2:151-66
Moyer, Adam L; Wagner, Kathryn R (2015) Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism. J Neuromuscul Dis 2:371-385
Huh, Yang Hoon; Noh, Minsoo; Burden, Frank R et al. (2015) Sparse feature selection identifies H2A.Z as a novel, pattern-specific biomarker for asymmetrically self-renewing distributed stem cells. Stem Cell Res 14:144-54
Lek, Angela; Rahimov, Fedik; Jones, Peter L et al. (2015) Emerging preclinical animal models for FSHD. Trends Mol Med 21:295-306
Zhang, Yuanfan; King, Oliver D; Rahimov, Fedik et al. (2014) Human skeletal muscle xenograft as a new preclinical model for muscle disorders. Hum Mol Genet 23:3180-8
Jones, Takako I; Yan, Chi; Sapp, Peter C et al. (2014) Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing. Clin Epigenetics 6:23

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