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Human Molecular Genetics Pages 589-595

Dystrophins in vertebrates and invertebrates
Introduction
Results And Discussion
   Amplification of vertebrate dystrophins
   Amplification of invertebrate dystrophins
   Phylogenetic analysis
   History of the dystrophin family
Materials And Methods
   Preparation of RNA and DNA
   RT-PCR and sequencing
   3' RACE
   Phylogenetic analysis
Abbreviations
Acknowledgements
References


Dystrophins in vertebrates and invertebrates

Dystrophins in vertebrates and invertebrates Roland G. Roberts1,2,* and Martin Bobrow1

1Department of Medical Genetics, Addenbrookes Hospital, Cambridge, UK and 2Division of Medical and Molecular Genetics, UMDS, Guy's Hospital, London, UK

Received October 30, 1997; Revised and Accepted December 23, 1997

DDBJ/EMBL/GenBank accession nos: X99700-X99702, X99736-X99738, X99757

Members of the dystrophin family of proteins perform a critical but incompletely characterized role in the maintenance of membrane-associated complexes at points of intercellular contact in many vertebrate cell types. They interact with, amongst others, the transmembrane laminin receptor dystroglycan, cytoskeletal actin and, indirectly, the intracellular membrane-associated signalling enzyme neuronal nitric oxide synthase (nNOS). Here we describe sequences of a range of dystrophin-related proteins from vertebrate and invertebrate animals (including the important model organism Drosophila melanogaster) and infer an evolutionary history of this family and its relationship to the distantly related dystrobrevins. It appears that most metazoa possess sequences encoding a single highly conserved dystrophin-like protein in addition to a presumed distinct dystrobrevin, derived from an early duplication of an ancestral gene. In the vertebrates (but not the protochordate Amphioxus), the single invertebrate dystrophin-like gene has undergone serial duplication to generate at least three distinct genes encoding proteins which have adopted specialized roles. It is hoped that this broadening of the biology of the dystrophins will afford further opportunities for the advancement of our understanding of the fundamental defect underlying the variety of human genetic disorders which result from aberrant or absent dystrophin-associated complexes.

INTRODUCTION

Dystrophin (1) is a large (427 kDa) protein which is highly conserved in vertebrates. Its largest isoform comprises an N-terminal domain which binds to F-actin, 24 spectrin-like repeats and a characteristic C-terminal set of domains. Although multiple isoforms are expressed widely in a complex tissue-specific manner (reviewed in ref. 2), null mutations in its gene which are expected to disrupt all protein isoforms tend to give a characteristic syndrome (Duchenne muscular dystrophy, DMD) of progressive skeletal and cardiac myopathy, electroretinopathy and a relatively specific form of mental retardation. Despite this well-known phenotype, the actual function of dystrophin remains unclear.

A number of related vertebrate proteins, whose function is even less clear, have been described. Utrophin (3) is very similar in overall structure to dystrophin itself, and its disruption in mice has been found to cause subtle abnormalities of the neuromuscular junction (4,5). Dystrophin-related protein 2 (DRP2; ref. 6) resembles certain small (~110 kDa) isoforms of dystrophin and utrophin in that it comprises the last two spectrin-like repeats and the C-terminal region. Dystrophin, utrophin and DRP2 are expressed in distinct but partially overlapping regions of the vertebrate body. The rather distantly related protein dystrobrevin (7), also known as 87K tyrosine kinase substrate (8) and A0 (10), retains sequences corresponding to the C-terminal 70 kDa of dystrophin. Dystrobrevin is widely expressed and binds to dystrophin, utrophin and, presumably, DRP2.

A number of motifs are recognizable in the C-terminal region of this family of proteins. The WW domain, which is missing from dystrobrevin, has been implicated in mediating the interaction between dystrophin and the transmembrane protein [beta]-dystroglycan (10). Motifs in the remaining C-terminal sequences comprise two EF hands, a ZZ domain with the ability to bind Zn2+, and two leucine heptad repeats. Between the ZZ domain and the leucine heptads is a region involved in binding members of the syntrophin family of PDZ domain-containing proteins (11,12), which in turn bind to neuronal nitric oxide synthase (nNOS) (13).

In this study, we set out to exploit the extraordinary degree of evolutionary sequence conservation of the C-terminal domains of the dystrophin family members in order to assess the history of these proteins and to investigate their prevalence in the animal kingdom.


Figure 1. (Opposite and overleaf) Alignment of known dystrophin- and dystrobrevin-related sequences, corresponding to amino acids 2703-3685 of human muscle-type dystrophin. Dots indicate identity to human dystrophin, dashes indicate gaps introduced to maximize similarity, open boxes delineate recognized structural or functional features, and shaded boxes indicate heptad leucine residues. `[Delta]78 C-Terminus' represents the putative translation of dystrophin 3' UTRs were the 32 nucleotides of exon 78 to be omitted as they are in certain human transcripts. Accession nos: H.sapiens dystrophin M18533, Mus musculus dystrophin M68859, G.gallus dystrophin X13369, X.laevis dystrophin X99700, T.californica dystrophin M37645, S.caniculus dystrophin X99702, H.sapiens utrophin X69086, M.musculus utrophin X83506, X.laevis utrophin X99701, S.caniculus utrophin X99703, H.sapiens DRP2 U43519, M.musculus DRP2 U43520, Gobius sp. DRP2 U43518, S.caniculus DRP2 U43517, B.lanceolatum IDLP X99736, Asteroidea sp. IDLP X99737, Pectinidae sp. IDLP X99738, D.melanogaster IDLP X99757, C.elegans EST C10048, H.sapiens [alpha]-dystrobrevin U46744, M.musculus dystrobrevin X95226 (omitted from this figure), T.californica dystrobrevin L06945.

RESULTS AND DISCUSSION

Amplification of vertebrate dystrophins

Known dystrophin-related sequences (Homo sapiens dystrophin, Mus domesticus dystrophin, Gallus gallus dystrophin, Torpedo californica dystrophin and H.sapiens utrophin) were used to direct the design of a set of degenerate primers which might permit the amplification of most related sequences which would have arisen since the divergence of the dystrophin and utrophin genes. These included the final set of nested primers, EVE/EVG (outer) and EVA/EVB (inner), which span a 1472 bp region between sequences encoding the WW domain (corresponding to amino acid 3085 of the human dystrophin sequence) and the second leucine heptad domain (amino acid 3575; see Materials and Methods). These primers successfully amplified dystrophin-like and utrophin-like sequences from Xenopus laevis and Scylliorhynus caniculus. 3' RACE with subsequent vectorette PCR was performed with the aim of obtaining the extreme 3' end of the coding region.

The two novel dystrophin sequences described here, from X.laevis and S.caniculus, hold no surprises. The Xenopus transcript, like that of chicken, lacks exon 72, presumably through alternative splicing. The S.caniculus sequence, unlike the published T.californica sequence, contains exon 71. More interestingly, the 3' ends of the novel sequences show that the region of the 3'-untranslated region (3' UTR) which is brought into register with the principal open reading frame by alternative splicing of the penultimate exon 78 (ref. 14; `[Delta]78' in Fig. 1) is highly conserved throughout vertebrates; indeed, this largely brain-specific `[Delta]78' C-terminus appears to be more highly conserved than is the conventional C-terminus, perhaps suggesting a unique role for this region. A significant degree of conservation continues for at least 400 bp further into the 3' UTR (data not shown).

To our knowledge, this is the first report of non-mammalian utrophin sequences. Although substantially more prone to variation than are the dystrophins, particularly between the two leucine heptad regions and at the C-terminus, they do exhibit a set of signature characteristics which set them apart from the dystrophins in structure and presumably in function.

Although no dystrophin-like or utrophin-like sequences were ever obtained from Gobius RNA, an unusual, more distantly related product was obtained. An aberrant band from amplification of S.caniculus RNA (generated by mispriming of EVB) also yielded sequence most closely related to the Gobius product. The clear relationship between these sequences, together with the simultaneous detection of three distinct dystrophin-related sequences in S.caniculus, persuaded us of the likelihood of discovering an orthologous sequence in mammals. The further characterization of this class of sequence, termed DRP2, has been described more fully elsewhere (6,15).

Amplification of invertebrate dystrophins

The novel sequences obtained using this initial set of primers were used to aid the design of a second set of primers corresponding to more highly conserved sequences (EVJ/EVM outer, and EVI/EVN inner; see Materials and Methods). These in turn enabled the amplification of single dystrophin-like sequences from RNA of Branchiostoma lanceolatum, Asteroidea sp., Pectinidae sp. and Drosophila melanogaster. No products were ever obtained from Lampetra (either adult or larval stage). 3' RACE with subsequent vectorette PCR was used to obtain 3' sequences at least as far as EVB in all these cases. Only in the case of D.melanogaster was it possible to complete the 3' end of the coding region. As D.melanogaster is an important model organism, we also attempted to obtain as much sequence 5' of EVA as possible, by performing vectorette PCR on a whole larval cDNA library. This yielded sequence encoding the C-terminal three spectrin-like repeats, in addition to the remainder of the WW domain. In addition, we used genomic PCR to determine the exon structure of the 3' region of the D.melanogaster gene; surprisingly, given that exon structure is highly conserved between dystrophin and DRP2, and even to a lesser extent dystrobrevin, the region encoded by the last 15 exons of the human dystrophin gene is encoded by a mere four exons in Drosophila (corresponding to: beginning of exon 65 to halfway through exon 67; halfway through exon 67 to end of exon 69; exon 70; and exon 72 to the end of the coding sequence). After this study was completed, a partial dystrophin-like expressed sequence tag (EST) from the nematode Caenorhabditis elegans was found during a database search using BLAST.

Phylogenetic analysis

Phylogenetic analysis of all characterized dystrophin-like proteins showed that sequences from vertebrate animals fall naturally into three clusters, namely dystrophins, utrophins and DRP2s. Bootstrap analysis supported these clusters in 100% of trials. Within each cluster, the branching follows the accepted phylogeny of organisms based on independent phenotypic and/or genotypic characters (see Fig. 2 and Table 1). It is evident that the divergence of these three members of the dystrophin family occurred before the vertebrate radiation (the three S.caniculus sequences are each clearly characteristic of their group), and that DRP2 diverged substantially earlier than did dystrophin and utrophin. It also appears that the dystrophin group is substantially less divergent than the other two (interspecific distances are approximately one-quarter those of the utrophin group), perhaps indicative of more stringent functional constraint on sequence variation. It is unfortunate, given that the protochordate B.lanceolatum appears to have only one dystrophin-like protein, that we were unable to obtain sequences from the evolutionarily intermediate agnathan vertebrate Lampetra in order to locate the point at which dystrophin and utrophin diverged from each other.


Table 1. Pairwise identities between known dystrophin-like proteins

Percentage identity between regions of known dystrophin-like proteins corresponding to amino acids 3085-3575 of human dystrophin.

The invertebrate sequences also seemed to follow the expected phylogeny, although bootstrap re-analysis lent rather weaker support to the optimal branch order (see Fig. 2). For the purpose of discussion, we have assumed that the sequences obtained represent the sole dystrophin-like entity in invertebrates (including the protochordates), and suggest the name IDLP (invertebrate dystrophin-like protein), as this protein is not strictly orthologous to any one of the vertebrate dystrophin-related proteins.

All of the sequences identified in this study resemble each other ( >= 45% identity) much more than they do the dystrobrevins (22-27% identity), and it is a parsimonious assumption that each of these organisms also possesses a dystrobrevin-like sequence which would not be expected to be amplified using our primer sets.

History of the dystrophin family

This study represents, to our knowledge, the first description of dystrophin-like sequences from invertebrate organisms. [Wang et al. (16), following the chance identification of a sea urchin homologue of dystrophin, have performed a detailed study of this protein and its gene, and have reached similar conclusions to our own regarding the evolution of the dystrophins.] The demonstration that dystrophin-like proteins appear to be highly conserved throughout metazoans lends strength to the suggestion that they play a fundamental role in animal biology. While it is not absolutely clear that the IDLP sequences represent strict orthologues of each other, they do seem to share a large number of characteristics given the diversity of the organisms of origin (each is from a different phylum). N-terminal to the WW domain of the Drosophila sequence, which has been characterized more fully, there lie at least three copies of the spectrin repeats, suggesting that IDLPs are likely to be larger than DRP2, and may even be of a similar size to dystrophin itself, complete with an N-terminal actin-binding domain.

From these data, and given the known interaction between vertebrate dystrophin and dystrobrevin, we can suggest the following evolutionary history of the dystrophin/dystrobrevin family of proteins (see corresponding ringed letters on Fig. 2). (a) A single ancestral gene in primitive metazoans encoded a protein which may have been active as a homodimer. (b) Duplication early in metazoan history gave single dystrophin-like (IDLP) and dystrobrevin-like sequences in most animal phyla. These are likely to exist in invertebrates as heterodimers of a perhaps long rod-like IDLP and a short dystrobrevin. (c) Duplication of the IDLP gene early in vertebrate evolution (before the divergence of cartilaginous and bony fish) yielded DRP2, expressed in the central nervous system, and a common ancestor of dystrophin and utrophin. At this point, only the 3' portion of the gene may have been duplicated, leaving the DRP2 branch without sequences encoding the actin-binding domain and most of the rod domain. (d) A second vertebrate-specific duplication of one of these genes resulted in distinct dystrophin and utrophin sequences. It appears that the dystrobrevin gene may not have been duplicated in either of these events. (e) It is possible, given the evidence for quadruplication of many genes between protochordates and vertebrates (17), that vertebrates possess a further as yet undetected dystrophin homologue (which might be termed DRP3) which would be as closely related to DRP2 as dystrophin is to utrophin.

MATERIALS AND METHODS

Preparation of RNA and DNA

Tissues were obtained from the amphibian X.laevis (brain, skeletal muscle, lung), the bony fish Gobius sp. (multiple tissue cross-section) and the cartilaginous fish S.caniculus (skeletal muscle). Whole bodies were obtained of the agnathan Lampetra (adult and ammocoete larva), the cephalochordate amphioxus, B.lanceolatum (adult), and examples of invertebrate phyla; echinoderm (Asteroidea sp.; starfish), mollusc (Pectinidae sp.; scallop) and arthropod (D.melanogaster; fruitfly). Samples were frozen on dry ice, ground in a chilled pestle and mortar, dissolved in solution D, and RNA extraction was performed according to ref. 18. Independent genomic DNA samples were prepared by using the same method but with the addition of sodium acetate at the higher pH of 5.2 (19).


Figure 2. Dendrogram of the dystrophin- and dystrobrevin-like sequences aligned in Figure 1. Shaded boxes delineate the four known vertebrate groups of orthologous sequences (H, human; M, mouse; X, Xenopus; T, Torpedo; D, dogfish). Ringed letters indicate events described in the text under `History of the dystrophin family'. Numbers at nodes represent, to the nearest percent, the percentage of 1000 bootstrap trials which supported that cluster (the C.elegans sequence, being shorter, could not be included in this analysis).

Table 2. Degenerate oligonucleotides used
Name Sequencea Directionb Positionc
EVA CARACNACNTGYTGGAYCA S 9443-9462
EVB TGRTCYTCNARDATYTGCAT A 10 934-10 953
EVE GTNCCNTAYTAYATNAAYCA S 9416-9435
EVG TCNARYTGYTTRTTRTGRTC A 10 949-10 968
EVI GTNGAYATGTGYYTNAAYTGG S 9731-9751
EVJ GTNCCNYTNTGYGTNGAYATG S 9719-9739
EVM GTYTGNACNGGNARRTANCC A 10 385-10 404
EVN CAYTTNGCYTGRTGYTTNGC A 10 127-10 146
aDegenerate bases are given according to IUPAC nomenclature.
bS/A, sense or antisense with respect to dystrophin mRNA sequence.
cPosition of sequence given in nucleotides with respect to the original published human dystrophin cDNA sequence (M18533).

RT-PCR and sequencing

Total RNA was subjected to reverse transcription and nested PCR as described in ref. 20, using degenerate oligonucleotide primers (Table 2, and see Results). Products of nested RT-PCR were purified from ethidium-stained agarose minigel slices using the GeneClean method (Bio101). Products were sequenced directly (21) using either degenerate primers or (after initial characterization) primers specific to the sequence under study (sequences available on request). In cases where a mixture of products was obtained (X.laevis, S.caniculus), these were subcloned into pBLUESCRIPT before sequencing. Sequence-specific primers were used to perform PCR of genomic DNA in order to confirm the species of origin of each transcript.

3' RACE

In cases where no sequence 3' of EVN was obtainable by conventional RT-PCR (Gobius sp. and S.caniculus DRP2, and sequences from B.lanceolatum, Asteroidea sp., Pectinidae sp. and D.melanogaster), modified 3' RACE (19,22) was performed. Attempts were also made to obtain sequences 3' of EVB from the dystrophin and utrophin transcripts of X.laevis and S.caniculus.

Phylogenetic analysis

Amino acid sequences from notional translation were aligned using CLUSTAL, and phylogenetic analysis was performed using the entire 491 amino acid region between EVA and EVB (corresponding to residues 3085-3575 of human dystrophin; PKMTELY......QHKGRLE) in the neighbour-joining method of CLUSTAL, followed by bootstrap re-analysis in order to ascertain the statistical strength of the given branch order; trees were drawn using RETREE and DRAWGRAM from the PHYLIP package. The limited sequence available from an EST from the nematode C.elegans was placed in the tree independently by performing a similar analysis of correspondingly shorter sequences. Parts of line eight of the alignment shown in Figure 1 were amended by eye to preserve known exon boundaries; although Figure 2 branch lengths and bootstrap scores were calculated using the computer-generated alignment, calculations using the visual alignment gave indistinguishable results.

ABBREVIATIONS

DMD, Duchenne muscular dystrophy; DRP2, dystrophin-related protein 2; EST, expressed sequence tag; IDLP, invertebrate dystrophin-like protein; nNOS, neuronal nitric oxide synthase; RACE, rapid amplification of cDNA ends; UTR, untranslated region.

ACKNOWLEDGEMENTS

We are greatly indebted to Dr Quentin Bone at the Marine Biological Laboratory, Plymouth, UK, for providing marine specimens, and to Lucy Nicholson for analysis of Xenopus sequences. This work was funded by a Special Training Fellowship from the Medical Research Council, by the Generation Trust and by the Muscular Dystrophy Group of Great Britain and Northern Ireland.

REFERENCES

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*To whom correspondence should be addressed at: Division of Medical and Molecular Genetics, UDMS, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Tel: +44 171 955 2527; Fax: +44 171 955 4644; Email: rroberts@hgmp.mrc.ac.uk

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