Role of Perlecan at the Neuromuscular Junction
	Perlecan is a major heparan sulfate proteoglycan in basement membrane and in some other tissues such as cartilage. Perlecan consists of a 400-kDa protein core, which can be divided into five distinct domains designated I-V. The protein core contains covalently attached glycosaminoglycan (GAG) chains at the N- and C-terminal domains. Perlecan has various biological activities, such as cell growth and differentiation, modulation of growth factor activity, and binding to many molecules, including extracellular matrices, growth factors, and cell surface receptors. Most of these activities have been identified in in vitro systems. However, recent studies with gene knockout mice and human genetic disorders provide some insights into the role of perlecan in development and tissue functions (1,2,3). We identified two classes of human genetic disorders (2,3). Functional-null mutations of perlecan cause a lethal chondrodysplasia, dyssegmental dysplasia, Silverman-Handmaker type (DDSH). Partially functional mutations of perlecan also cause Schwartz-Jampel syndrome (SJS), characterized by myotonia and chondrodysplasia. Perlecan is present in muscle basement membranes and is enriched at the neuromuscular junction (NMJ). At the NMJ, the nicotinic acetylcholine (ACh) receptor mediates postsynaptic depolarization by activating Na channels, and induces muscle contraction. Acetylcholinesterase (AChE) terminates this process by hydrolyzing ACh and regulating muscle relaxation and recycling of ACh. The collagen-tail form of AChE is preferentially expressed in innervated regions of muscles and is shown to bind perlecan in vitro. In the perlecan knockout mice, muscle development and differentiation appear to be normal and normal nerve terminals are formed at birth (4). Clustering molecules are present at the NMJ of the mutant mouse muscles. However, AChE is absent in newborn NMJ, although AChE protein is synthesized normally. Thus, perlecan is essential for localizing AChE at the NMJ. This function may explain myotonia phenotype observed in SJS patients. Creating a new animal model will be useful to study the mechanism of myotonia of SJS and therapeutic reagents.
Fig.1 Role of Perlecan at the Neuromuscular Junction
	Eri Hirasawa (Department of Neurology, Juntendo University School of Medicine)
	References (1) Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y: Perlecan is essential for cartilage and cephalic development. Nat. Genet. 23, 354-358, 1999 (2) Arikawa-Hirasawa E, Wilcox WR, Le AH, Silverman N, Govindraj P, Hassell JR, Yamada Y: Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nat. Genet. 27, 431-434, 2001 (3) Arikawa-Hirasawa E, Le AH, Nishino I, Nonaka I, Ho NC, Francomano CA, Govindraj P, Hassell JR, Devaney JM, Spranger J, Stevenson RE, Iannaccone S, Dalakas MC, Yamada Y: Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. Am. J. Hum. Genet. 70, 1368-1375, 2002 (4) Arikawa-Hirasawa E, Rossi SG, Rotundo RL, Yamada Y: Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice. Nat. Neurosci. 5, 119-123, 2002 Linlks PG-A09 Basement Membrane Proteoglycans (Takashi Saku)
Aug. 6, 2004