chapter  4
Protein interactions, right or wrong, in Emery-Dreifuss muscular dystrophy
ByGlenn E. Morris
Pages 13

The English idiom of ‘not being able to see the wood for the trees’ is somewhat ambiguous. It could mean that one cannot recognize the presence of a wood under bark and leaves, or, more often, that one spends so much time looking at individual trees that one cannot see the broader picture-the wood or forest-that the trees create. Either way, this is a common problem in trying to understand the molecular pathogenesis of EmeryDreifuss muscular dystrophy (EDMD) and related laminopathies. So many surprising facts emerge that it is difficult to identify which are important clues and which are relatively trivial for understanding the disease process. Is it possible to account for all the disparate observations with a simple molecular hypothesis? Emery-Dreifuss muscular dystrophy is most commonly an X-linked form (X-EDMD) caused by complete absence of the nuclear membrane protein, emerin (Bione et al., 1995; Manilal et al., 1996; Nagano et al., 1996). Rather less common is an autosomal dominant form (AD-EDMD) caused by missense mutations in lamin A/C (Bonne et al., 1999). Why do these mutations affect skeletal and cardiac muscles and cause joint contractures while other tissues are functionally unaffected (Emery, 1993)? Is it significant that conducting cells in the heart are preferentially affected, compared to contractile cells? Some muscles in EDMD are only mildly affected while others may become severely wasted. Not unnaturally, EDMD muscle biopsies are usually taken from mildly affected muscles rather than severely wasted ones and they show a mild histopathology with evidence of regeneration but little or no necrosis (Sewry, 2000; Sewry et al., 2001). There is also frequent clinical variability in EDMD, even within families with the same mutation. The variability may be in both the range of clinical features displayed and their severity and is usually attributed to individual genetic background (modifying genes), although environmental effects have not been ruled out (Morris, 2001). Variability has probably confused the clinical distinction between the X-linked form of EDMD and the autosomal dominant form caused by missense mutations in lamin A/C. The two forms of the disease were once thought to be indistinguishable clinically, but it is now clear that the cardiac problem in AD-EDMD is more severe (Becane et al., 2000). Sudden cardiac death is more common in AD-EDMD patients and they often develop a dilated cardiomyopathy that requires a heart transplant, whereas transplants are very rarely performed in X-

EDMD. Systematic comparisons of skeletal muscle wasting and contracture severities in the two forms of the disease have not yet been reported. A large proportion of patients with the clinical features of EDMD have no mutations in either emerin or lamin A/C. There is at least one family with autosomal inheritance and this suggests that mutations in a third gene can cause EDMD. Most such cases, however, are sporadic with no family history of EDMD. This might suggest the possibility of a non-genetic origin in these cases, but a large number of sporadic cases do have lamin A/C mutations that are presumably responsible for the disease (Bonne et al., 2000). How many of these observations will be critical clues in developing an explanation of the molecular pathogenesis and how many are irrelevant remains to be seen.