Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse.

Abstract

We have previously reported a dystrophinrelated locus (DMDL for Duchenne muscular dystrophy-like) on human chromosome 6 that maps close to the dy mutation on mouse chromosome 10. Here we show that this gene is expressed in a wide range of tissues at varying levels. The transcript is particularly abundant in several human fetal tissues, including heart, placenta, and intestine. Studies with antisera raised against a DMDL fusion protein identify a 400,000 Mr protein in all mouse tissues tested, including those of mdx and dy mice. Unlike the dystrophin gene, the DMDL gene transcript is not differentially spliced at the 3' end in either fetal muscle or brain.Dystrophin has been identified as the protein product defective in Duchenne muscular dystrophy (DMD); however, very little is known about its precise function (1-3). Sequence comparisons have revealed features in common with cytoskeletal proteins. The amino-terminal region of dystrophin shows homology to the actin binding region of a-actinin (4,5) and the central rod domain shows structural similarities to the triple helical configuration of spectrin (6). In contrast, the carboxyl-terminal domain of 420 amino acids does not show homology to any previously characterized proteins. This latter domain is thought to be important in the integration of dystrophin into a glycoprotein complex localized at the muscle membrane surface (7,8). The carboxyl-terminal region of the gene is differentially spliced in muscle and brain, which suggests the production of isoforms with differing interactions with membrane proteins (9). In addition, this region of dystrophin is important for the correct functioning of the molecule in vivo as deletions covering this domain result in DMD rather than the milder Becker muscular dystrophy (10)(11)(12)(13).Recently, we demonstrated the existence of an mRNA in human fetal muscle that shares a high degree of sequence homology with the carboxyl-terminal region of dystrophin (14). The gene encoding this transcript is localized to human chromosome 6 and the locus has been designated DMDL for DMD-like in Human Gene Mapping 10 (15). The DMDL gene shares structural similarities with dystrophin: the transcript is large, 13 kilobases (kb), and is multiexonic with a similar distribution of 3' exons and introns.Although no human disease has yet been attributed to mutations at the DMDL locus, the mouse homologue of this gene, designated Dmdl, has been shown to be syntenic with the dy (dystrophia muscularis) locus on mouse chromosome 10 (16). The dy mutation is recessive and results in a severe neuromuscular disease in the mouse in which skeletal muscle shows degenerative changes (17). These observations suggest that the Dmdl gene may be a candidate for the dy mutation.In this paper, we present the tissue distribution of the DMDL transcript in humans and compare this distribution with the presence of a 400,000 Mr protein in mouse tissues. We also investigate the occurrence ofthe DMDL polypeptide in liver and muscle of mice with mutations in the dy...

Expression of Agrin, Dystroglycan, and Utrophin in Normal Renal Tissue and in Experimental Glomerulopathies

“…Several studies have already shown that utrophin is present near BMs in many tissues, 64 -67 including the kidney. 20 In the present study we found staining for utrophin in some but not all of the podocyte foot processes. That not all foot processes were positive could be due to low affinity of the mAb (DRP-2), because staining in IF was weak as well (see Figure 2D).…”

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

“…Taken together, our observation support the proposal that the recruitment of utrophin and other DAPC components to the membrane is the mechanism by which rhBGN counters dystrophic pathology in mdx mice. It is of particular note that total utrophin protein levels are up-regulated in DMD muscle (37)(38)(39). Therefore rhBGN can be expected to be effective in DMD patients.…”

Dystroglycan mRNA expression during normal and mdx mouse embryogenesis: A comparison with utrophin and the apo‐dystrophins

“…This view is supported by the high level of sequence homology between utrophin and dystrophin in the carboxyl terminal region, which is involved in dystroglycan binding (Tinsley et al, 1992;Suzuki et al 1992), and by the observation that in dystrophin-deficient large calibre skeletal muscle dystroglycan is retained only at the neuromuscular junction (Matsumura et al, 1992), a site where utrophin is abundantly expressed . While little is known of the tissue distribution of dystroglycan in development and whether it colocalizes with utrophin, it is clear that both dystroglycan and utrophin show a wider distribution in adult tissues than dystrophin, for example both are abundant in some non-muscle sites such as lung and kidney (Love et al, 1991;Ibraghimov-Beskrovnaya et al, 1993). Very recently we described a short transcript of utrophin, which is the structural homologue of Dp 116 (apo-dystrophin-21, and is expressed exclusively in sensory ganglia and brain.…”