The dystrophin/utrophin homologues in Drosophila and in sea urchin

The gene which is defective in Duchenne muscular dystrophy (DMD) is the lar gest known gene containing at least 79 introns, some of which are extremely large. The product of the gene in muscle, dystrophin, is a 427 kDa protein . The same gene encodes at least two additional non-muscle full length dyst rophin isoforms transcribed from different promoters located in the 5'-end region of the gene, and four smaller proteins transcribed from internal pro moters located further downstream, and lack important domains of dystrophin . Several other genes, encoding evolutionarily related proteins, have been identified. To study the evolution of the DMD gene and the significance of its various products, we have searched for genes encoding dystrophin-like p roteins in sea urchin and in Drosophila. We previously reported on the char acterization of a sea urchin gene encoding a protein which is an evolutiona ry homologue of Dp116, one of the small products of the mammalian DMD gene, and on the partial sequencing of a large product of the same gene. Here we describe the full-length product which shows strong structural similarity and sequence identity to human dystrophin and utrophin. We also describe a Drosophila gene closely related to the human dystrophin gene. Like the huma n gene, the Drosophila gene encodes at least three isoforms of full length dystrophin-like proteins (dmDLP1, dmDLP2 and dmDLP3,), regulated by differe nt promoters located at the 5' end of the gene, and a smaller product regul ated by an internal promoter (dmDp186). As in mammals, dmDp186 and the dmDL Ps share the same C-terminal and cysteine-rich domains which are very simil ar to the corresponding domains in human dystrophin and utrophin. In additi on, dmDp186 contains four of the spectrin-like repeats of the dmDLPs and a unique N-terminal region of 512 amino acids encoded by a single exon. The f ull length products and the small product have distinct patterns of express ion. Thus, the complex structure of the dystrophin gene, encoding several l arge dystrophin-like isoforms and smaller truncated products with different patterns of expression, existed before the divergence between the protosto mes and deuterostomes. The conservation of this gene structure in such dist antly related organisms, points to important distinct functions of the mult iple products. (C) 2001 Elsevier Science B.V. All rights reserved.