A SEA-URCHIN GENE ENCODING DYSTROPHIN-RELATED PROTEINS

The gene which is defective in Duchenne muscular dystrophy (DMD) is th e largest known gene. The product of the gene in muscle, dystrophin, i s a 427 kDa protein. The same gene encodes at least six additional pro ducts: two non-muscle dystrophin isoforms transcribed from promoters l ocated in the 5'-end region of the gene and four smaller proteins tran scribed from internal promoters located further downstream. Several ot her genes, encoding evolutionarily related proteins, have been identif ied. These include a structurally very similar gene in vertebrates enc oding utrophin (DRP1), which is closely related to dystrophin, and a n umber of small and simple genes in vertebrates or invertebrates encodi ng proteins similar to some of the small products of the DMD gene. We have isolated a sea urchin gene showing very strong sequence and struc tural homology with the DMD and utrophin genes. Sequence and intron/ex on structure similarities suggest that this gene is related to a precu rsor of both the DMD gene and the gene encoding utrophin. The sea urch in gene has the unique complex structure of the DMD gene. There is at least one, and possibly more, product(s) transcribed from internal pro moters, as well as a large product of >300 kDa containing at least thr ee of the four major domains of dystrophin. The small product seems to be evolutionarily related to Dp116, one of the small products of the human DMD gene. Partial characterization of this gene helped us to con struct an evolutionary tree connecting the vertebrate dystrophin gene family with related genes in invertebrates. The constructed evolutiona ry tree also implies that the vertebrate small and simple structured g ene encoding a Dp71-like protein, called DRP2, evolved from the dystro phin/utrophin ancestral large and complex gene by a duplication of onl y a small part of the gene.