The broad and long-term goal of this application is to identify the molecular mechanisms that cause facioscapulofaciohumeral dystrophy (FSHD). The broad hypothesis is that deletion of a subset of the D4Z4 units on 4qA161 results in increased or aberrant transcription from the remaining D4Z4 units on the deleted allele. Our preliminary studies have identified multiple sense and anti-sense transcripts from the D4Z4 unit. We have characterized one of the polyadenylated D4Z4 sense transcripts and developed assays to demonstrate its biological function. The specific goal of this application is to determine whether the protein product of a D4Z4 transcript causes FSHD.
Aim 1 will characterize sense and anti-sense transcripts from pathogenic and non-pathogenic D4Z4 alleles, their potential protein products, and their expression relative to FSHD.
Aim 2 will test the hypothesis that the polyadenylated RNA transcripts from the D4Z4 locus encode several distinct proteins, including the full-length DUX4 and splice-isoforms of DUX4, each with specific developmental biological functions in myogenesis, and that these functions contribute to FSHD pathology.
Aim 3 will characterize the IRES element of the DUX4 RNA and test a new hypothesis regarding transitions between RNA translational programs during myogenic differentiation. Together, these studies will advance our knowledge regarding the pathophysiology of FSHD and muscle cell biology.

Public Health Relevance

The human health relatedness of this proposal is that it will identify possible molecular causes of FSHD and provide a basis for future therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045203-12
Application #
8019025
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
1998-09-01
Project End
2015-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
12
Fiscal Year
2011
Total Cost
$372,742
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
van den Boogaard, Marlinde L; Lemmers, Richard J F L; Camaño, Pilar et al. (2016) Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2. Eur J Hum Genet 24:78-85
Feng, Qing; Snider, Lauren; Jagannathan, Sujatha et al. (2015) A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. Elife 4:
Lemmers, Richard J L F; Goeman, Jelle J; van der Vliet, Patrick J et al. (2015) Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet 24:659-69
Balog, Judit; Thijssen, Peter E; Shadle, Sean et al. (2015) Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 10:1133-42
Yao, Zizhen; Snider, Lauren; Balog, Judit et al. (2014) DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet 23:5342-52
Sacconi, Sabrina; Lemmers, Richard J L F; Balog, Judit et al. (2013) The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 93:744-51
Young, Janet M; Whiddon, Jennifer L; Yao, Zizhen et al. (2013) DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet 9:e1003947
Krom, Yvonne D; Thijssen, Peter E; Young, Janet M et al. (2013) Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. PLoS Genet 9:e1003415
Balog, Judit; Thijssen, Peter E; de Greef, Jessica C et al. (2012) Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. Epigenetics 7:579-84
Krom, Yvonne D; Dumonceaux, Julie; Mamchaoui, Kamel et al. (2012) Generation of isogenic D4Z4 contracted and noncontracted immortal muscle cell clones from a mosaic patient: a cellular model for FSHD. Am J Pathol 181:1387-401

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