FSHD Related Defects in Human Myogenesis

Investigators: Daniel G Miller MD PhD, Stephen Tapscott MD PhD

Category: Research - Basic

Recent analysis of human gene expression arrays probed with RNA from muscle biopsies of FSHMD patients and control individuals affected with other types of muscular dystrophy indicate that FSHMD may be distinguished from other muscular dystrophies by specific defects in muscle cell differentiation. While analysis of muscle biopsies might reflect a natural picture of gene expression, averaging gene expression levels from multiple cell types present in muscle tissue, and multiple stages of muscle cell differentiation might also obscure dramatic deficiencies in specific subprograms of gene expression. Here we utilize a previously developed model of muscle cell differentiation to investigate the cause of FSHMD specific gene dysregulation and study molecular consequences of D4Z4 repeat contractions in cultured human cells. In a collaborative effort we will confirm previously described gene expression phenotypes in this model, evaluate regulatory sequences of genes showing unique expression patterns in FSHMD muscle biopsies, and evaluate transcription from the D4Z4 locus and surrounding regions. These experiments will form the basis of individual proposals to the NIH for funding of continued FSHMD research.

Statement of Hypothesis and Specific Aims.

The association of FSHMD and D4Z4 repeat contractions at 4q35 has been known for some time however the molecular consequence of these contractions is not understood. Recently we (SJT) and others have observed differences in muscle specific gene expression when comparing samples from FSHMD patients to age matched controls having other types of muscular dystrophy or no muscle disease (Winokur et al., 2003b). Many of the genes having disease specific expression patterns are known members of the myogenic differentiation pathway and direct targets of the MyoD transcription factor leading us and others to hypothesize that aberrant muscle cell differentiation may be an important feature of FSHMD. We propose to confirm similar gene expression differences in cell culture by probing gene expression arrays with RNA from controls and FSHMD patient fibroblasts undergoing MyoD induced differentiation, analyze the regulatory regions of aberrantly expressed genes using computer algorithms, and extensively search for products of transcription originating from the D4Z4 repeat and surrounding regions in differentiating cells.

Related Material

Publication: Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene.

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