Congenital Muscular Dystrophies: Toward Molecular Therapeutic Interventions

Abstract

Congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of neuromuscular disorders that typically present at birth or in early infancy with hypotonia, weakness, and histologic evidence of a dystrophic myopathy. CMD biochemical types include various abnormalities of alpha-dystroglycan O-mannosyl glycosylation as well as defects in integrin matrix receptors, the extracellular matrix proteins laminin-alpha(2) and collagen VI, nuclear proteins such as lamin A/C, and a protein of the endoplasmic reticulum, selenoprotein N. Current therapies are directed mostly at supportive care; however, recent advances in biotechnology and increased knowledge of the pathophysiology underlying the various CMD types have helped identify potential therapeutic strategies directed at genetic, molecular, and biochemical pathways involved in these disorders. In this article, we review our current understanding of the molecular pathogenesis of several CMD types and how these mechanisms may be therapeutically targeted.

ROCK1-directed basement membrane positioning coordinates epithelial tissue polarity

“…Loss of normal tissue organization is a defining characteristic of many diseases and can be a prerequisite for the development of disease (Bissell et al, 2003;Chapin and Caplan, 2010;Collins and Bonnemann, 2010). Epithelial tissue organization is established during development when cells acquire apicobasal polarity (Bryant and Mostov, 2008;Nelson, 2003).…”

Possible Diverse Roles of Fukutin: More Than Basement Membrane Formation?

“…From a therapeutic standpoint, many new strategies are underway for muscular dystrophy, particularly Duchenne muscular dystrophy (Collins & Bönnemann 2010;Cossu & Sampaolesi 2007;Muntoni et al 2007;Odom et al 2007). For -dystroglycanopathy, full restoration of -DG glycosylation might not be required (Kanagawa et al 2009).…”

“…For -dystroglycanopathy, full restoration of -DG glycosylation might not be required (Kanagawa et al 2009). Gene delivery using adeno-associated virus vectors may be applicable because causative genes of -dystroglycanopathy are small enough to be packaged into this vector (Collins & Bönnemann 2010;Odom et al 2007). Gene therapy using LARGE may be one of the candidates because gene transfer of LARGE restores -DG receptor function not only in Large myd mice but also in cultured cells from FCMD, MEB and WWS patients (Barresi et al 2009).…”

“…Gene therapy using LARGE may be one of the candidates because gene transfer of LARGE restores -DG receptor function not only in Large myd mice but also in cultured cells from FCMD, MEB and WWS patients (Barresi et al 2009). Transgenic overexpression of T-cell GalNAc transferase (GALgt2) in the skeletal muscle increases glycosylation of -DG (Collins & Bönnemann 2010;Yoon et al 2009). Transfer of fukutin restores glycosylation of -DG in knock-in mice carrying the retrotransposal insertion in the mouse fukutin ortholog (Kanagawa et al 2009).…”

The attachment disorders of muscle: failure to carb-load

“…Mutations in seven different genes that encode known or suspected glycosyltransferases lead to congenital muscular dystrophy (1). The congenital muscular dystrophies may be evident at birth, often presenting as floppy infant syndrome with reduced muscle tone (2). Progressive muscle degeneration is variably present in the congenital muscular dystrophies and may be accompanied by extramuscular features including eye and brain defects.…”