The importance of dystrophin and its associated proteins in normal muscle function is now well established. Many of these proteins are expressed in nonmuscle tissues, particularly the brain. Here we describe the characterization of ␤-dystrobrevin, a dystrophin-related protein that is abundantly expressed in brain and other tissues, but is not found in muscle. ␤-dystrobrevin is encoded by a 2.5-kb alternatively spliced transcript that is found throughout the brain. In common with dystrophin, ␤-dystrobrevin is found in neurons of the cortex and hippocampal formation but is not found in the brain microvasculature. In the brain, ␤-dystrobrevin coimmunoprecipitates with the dystrophin isoforms Dp71 and Dp140. These data provide evidence that the composition of the dystrophinassociated protein complex in the brain differs from that in muscle. This finding may be relevant to the cognitive dysfunction affecting many patients with Duchenne muscular dystrophy.

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Dystrophin coordinates the assembly of a complex of structural and signaling proteins that are required for normal muscle function. A key component of the dystrophin protein complex is ␣-dystrobrevin, a dystrophinassociated protein whose absence results in neuromuscular junction defects and muscular dystrophy. To gain further insights into the role of ␣-dystrobrevin in skeletal muscle, we used the yeast two-hybrid system to identify a novel ␣-dystrobrevin-binding partner called syncoilin. Syncoilin is a new member of the intermediate filament superfamily and is highly expressed in skeletal and cardiac muscle. In normal skeletal muscle, syncoilin is concentrated at the neuromuscular junction, where it colocalizes and coimmunoprecipitates with ␣-dystrobrevin-1. Expression studies in mammalian cells demonstrate that, while ␣-dystrobrevin and syncoilin associate directly, overexpression of syncoilin does not result in the self-assembly of intermediate filaments.Finally, unlike many components of the dystrophin protein complex, we show that syncoilin expression is upregulated in dystrophin-deficient muscle. These data suggest that ␣-dystrobrevin provides a link between the dystrophin protein complex and the intermediate filament network at the neuromuscular junction, which may be important for the maintenance and maturation of the synapse.

SummaryCommon variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.