Leiden Muscular Dystrophy pages

The Invertebrate Dystrophin Complex

Contributed by Roland G. Roberts and Marc J. Greener

(last modified on March 18, 2001)

Many biological problems of the vertebrates have benefited from complementary studies which exploit the experimental amenability and genetic simplicity of invertebrate organisms. The muscular dystrophies are no exception.

The recognition that all vertebrates seem to have well-defined sequences encoding dystrophin, utrophin and DRP2 (Roberts et al., 1996) stimulated a search for ancestral sequences in invertebrates. Perhaps unsurprisingly, given the high degree of conservation of the vertebrate proteins, recognisable dystrophin-like sequences were identified in sea urchin (Wang et al., 1998) and in amphioxus, sea squirt, starfish, scallop, fruit fly and nematode (Roberts & Bobrow, 1998).

In each case, phylogenetic analysis showed the invertebrate dystrophins to be orthologues of the last common ancestor of dystrophin, utrophin and DRP2. Thus, as with many other protein families, the radiation of the vertebrates is marked by multiple duplication of the single ancestral gene. It was also found that, at least for sea urchin (Wang et al., 1998), nematode (Bessou et al., 1998) and fruit fly (Greener & Roberts, 2000), the ancestral protein more resembles the giant rod-like proteins dystrophin and utrophin than the shorter DRP2.

Given the diversity of the remainder of the components of the vertebrate dystrophin complex, how much simpler is its invertebrate counterpart ?  The release of the more-or-less complete sequence of the Drosophila genome has afforded the opportunity to assess the invertebrate repertoire of dystrophin complex components, using a combination of in vitro and in silico techniques (Greener &  Roberts, 2000).

The basic findings are summarised below:

  1. The principal components are all retained, and regions implicated in intermolecular interactions are particularly highly conserved. This suggests that the overall form of the complex is conserved throughout metazoa.
  2. Drosophila has a single dystrophin/utrophin/DRP2 orthologue (DmDYS). Apart from its slightly shorter rod domain, it retains all the features of vertebrate dystrophin and utrophin. It is encoded by a gene in excess of 130 kb which has an idiosyncratic exon structure (more details).
  3. Drosophila has a single dystrobrevin (DmDYB), equally related to human alpha- and beta- dystrobrevins.
  4. Rather than the current tally of five vertebrate syntrophins (alpha-1, beta-1, beta-2, gamma-1, gamma-2), Drosophila has only two (the alpha/beta-like syntrophin-1 [DmSYN1] and the gamma-like syntrophin-2 [DmSYN2]).
  5. The phylogenetic trees for known members of the dystrophin/dystrobrevin family and the syntrophin family have strikingly identical topologies. Each indicates an ancient pre-metazoan duplication (to give two distantly related invertebrate proteins) followed by two recent duplications (to give 2+3=5 vertebrate proteins).
  6. As is assumed for vertebrates, Drosophila has only single genes encoding dystroglycan (DmDG) and beta-sarcoglycan (DmSCG-beta).
  7. There is a single common orthologue of vertebrate alpha- and epsilon-sarcoglycan (DmSCG-alpha/epsilon). Perhaps more surprisingly, there is only a single orthologue of gamma- and delta-sarcoglycan (DmSCG-gamma/delta); this is consistent with the finding that mammalian smooth muscle does not express gamma-sarcoglycan (Straub et al., 1999). The fly sarcoglycan complex is therefore expected to comprise only three distinct proteins.
  8. No Drosophila orthologue of sarcospan was apparent.
  9. Drosophila was presented as a model organism for the functional study of the dystrophin complex, as a potential complement to the recent studies in the nematode (C. elegans, Bessou et al., 1998 / Giugia et al., 1999).

Sequences: database links to Drosophila sequences

Gene  (symbol) cDNA sequence Genomic sequence Protein sequence
dystrophin / utrophin / DRP2 orthologue  (DYS)
(more details)
(5' incomplete)
AC008192 + AC007815 AAG17395
dystrobrevin  (DYB) AF277387   AAG17396
alpha/beta-like syntrophin (SYN1) AF277388   AAG17397
gamma-like syntrophin  (SYN2) AF277389   AAG17398
dystroglycan  (DG) AF277390   AAG17399
beta-sarcoglycan  (SCG-beta) AF277392   AAG17401
alpha- and epsilon-sarcoglycan  (SCG-alpha/epsilon) AF277391   AAG17400
gamma- and delta-sarcoglycan  (SCG-gamma/delta) AF277393   AAG17402
sarcospan - - -

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