Intracellular trafficking of emerin

Emery-Dreifuss muscular dystrophy (EDMD; OMIM # 310300) is an X-linked disease characterized by early contractures of the elbows, Achilles’ tendons and posterior neck, slow progressive muscle wasting and cardiomyopathy with atrioventricular conduction block (Emery and Dreifuss, 1966; Rowland et al., 1979; Emery, 1989). Positional cloning has identified a gene on chromosome Xq28 that is mutated in individuals with EDMD (Bione et al., 1994). The protein encoded by this gene, called emerin, is a type II integral membrane protein of 254 amino acids, with a 219 amino acid amino-terminal domain followed by a 21 amino acid transmembrane segment 11 residues from the carboxyl terminus (Bione et al., 1994). Emerin, which when mutated or absent is associated with a skeletaland heart-muscle specific phenotype, is expressed in the inner nuclear membrane of virtually all somatic cells and absent from this location in most individuals with EDMD (Manilal et al., 1996; Nagano et al., 1996). A phenotypically similar disorder(s) with cardiac condition abnormalities as a prominent feature is inherited in an autosomal dominant manner (Miller et al., 1985; Gilchrist and Leshner, 1986; Emery, 1989). Recently, mutations in the Lamin A/C gene have been found in individuals with this form of EDMD (Bonne et al., 1999). The inner nuclear membrane is one of three distinct membrane domains of the interphase nuclear envelope. On its nucleoplasmic face it is associated with the nuclear lamina, an intermediate filament meshwork composed of proteins called lamins (Aebi et al., 1986; Fisher et al., 1986; McKeon et al., 1986). Five integral membrane proteins, some with multiple isoforms generated by alternative RNA splicing, have so far been identified as specifically localized to the inner nuclear membrane in interphase. These five proteins are emerin (Manilal et al., 1996; Nagano et al., 1996), lamin B receptor (LBR) (Worman et al., 1988, 1990; Ye and Worman, 1994), lamina associated polypeptide (LAP)1 (Senior and Gerace, 1988; Martin et al., 1995), LAP2/thymopoietin (Foisner and Gerace, 1993; Harris et al., 1994; Furukawa et al., 1995) and MAN1 (F. Lin, D. L. Blake, I. Callebaut, I. S. Skerjanc, M. W. McBurney, M. Paulin-Levasseur and H. J. Worman, unpublished). The precise functions of these proteins remain to be determined, but LBR, LAP1 isoform C and LAP2/thymopoietin-β have been shown to bind lamins and 1709 Journal of Cell Science 112, 1709-1719 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0370