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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-S (57))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
United States
Zip Code
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
Mitsuhashi, Hiroaki; Mitsuhashi, Satomi; Lynn-Jones, Taylor et al. (2013) Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Hum Mol Genet 22:568-77
Rahimov, Fedik; Kunkel, Louis M (2013) The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol 201:499-510
Homma, Sachiko; Chen, Jennifer C J; Rahimov, Fedik et al. (2012) A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function. Eur J Hum Genet 20:404-10
Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey Boone (2011) Peripheral nerve pathology, including aberrant Schwann cell differentiation, is ameliorated by doxycycline in a laminin-?2-deficient mouse model of congenital muscular dystrophy. Hum Mol Genet 20:2662-72
Reed, Patrick W; Bloch, Robert J (2011) Crystallin-gazing: unveiling enzymatic activity. J Neurochem 118:315-6
Roche, Joseph A; Ford-Speelman, Diana L; Ru, Lisa W et al. (2011) Physiological and histological changes in skeletal muscle following in vivo gene transfer by electroporation. Am J Physiol Cell Physiol 301:C1239-50
Rahimov, Fedik; King, Oliver D; Warsing, Leigh C et al. (2011) Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor. Physiol Genomics 43:398-407
Arashiro, Patricia; Eisenberg, Iris; Kho, Alvin T et al. (2009) Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers. Proc Natl Acad Sci U S A 106:6220-5
Vishnudas, Vivek K; Miller, Jeffrey Boone (2009) Ku70 regulates Bax-mediated pathogenesis in laminin-alpha2-deficient human muscle cells and mouse models of congenital muscular dystrophy. Hum Mol Genet 18:4467-77