Isolation and characterization of a genomic clone from the murine utrophin locus.

Abstract

Dystrophin is a large 427-kDa cytoskeletal muscle protein localized to the inner surface of the sarcolemma (Hoffman et al. 1987; Koenig et al. 1988; Minetti et al. 1992). Sequence studies have shown that dystrophin consists of four functionally distinct domains--an N-terminal a-actin binding domain, a central rod-like triple helical repeat domain, a cysteine-rich domain, and a C-terminal domain (Koenig et al. 1988). The C-terminal domain appears to interact with an oligomeric complex of glycoproteins in the plasma membrane (Campbell and Kahl 1989), and it has been proposed that this interaction is responsible for anchoring dystrophin to the sarcolemma. However, some Duchenne muscular dystrophy patients who carry C-terminal deletions in dystrophin demonstrate correct localization of the truncated dystrophin at the sarcolemma (Helliwell et al. 1992). Nevertheless, absence of dystrophin leads to a reduction in dystrophinassociated glycoproteins, and, furthermore, it has been reported recently that a deficiency of one of the dystrophin-associated glycoproteins may be involved in severe childhood autosomal recessive muscular dystrophy (Matsumura et al. 1992). An autosomal homolog to dystrophin (Love et al. 1989; Tinsley et al. 1992), named utrophin, encodes a functionally distinct protein that shows homology to dystrophin over the entire coding region. However, particularly strong conservation is found in those C-terminal domains that are presumed to be involved with membrane association in dystrophin. In human the utrophin gene maps to Chromosome (Chr) 6 (Love et al. 1989), and in mouse, with a human utrophin cDNA, a homologous gene (Dmdl) has been mapped