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Emery-Dreifuss muscular dystrophy 1 (EDMD1)

This is transmitted as an X-linked recessive trait. The responsible gene on chromosome Xq28 was identified by Toniolo and colleagues and originally given the symbol STA and now EMD (Bione et al 1994). It encodes 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. Emerin was subsequently localized to the inner nuclear membrane (Manilal et al 1996; Nagano et al 1996). Emerin is expressed in most terminally differentiated somatic cells but absent in almost all patients with EDMD1.

More than 150 mutations are deposited in a mutation database. In addition to classical Emery-Dreifuss muscular dystrophy, phenotypic variants have been reported in patients with EMD mutations (Muntoni et al 1998; Astejada et al 2007; Ura et al 2007). Bione and colleagues and Nagano and colleagues invariably found lack of emerin in cardiac and skeletal muscles in patients with EDMD1, demonstrating that absence of protein on muscle biopsy can be diagnostic (Bione et al 1995; Nagano et al 1996). As emerin is also expressed in other tissues, its absence from skin cells and in buccal smear cells can also be used for diagnostic purposes, including carrier detection (Manilal et al 1997).

The Genetics of of EDMD


Emery-Dreifuss muscular dystrophy 2 (EDMD2)

EDMD2 is inherited in an autosomal dominant manner. Bonne and colleagues originally identified mutations in LMNA on chromosome 1q21 affected individuals in 6 families with autosomal dominant Emery-Dreifuss muscular dystrophy (Bonne et al 1999). LMNA encodes A-type nuclear lamins, the major somatic cell isoforms being lamin A and lamin C, which arise by alternative splicing of RNA from this gene (Lin and Worman 1993). Lamin A and lamin C are intermediate filament proteins that are components of the nuclear lamina, a protein meshwork localized to the inner aspect of the inner nuclear membrane (Aebi et al 1986; Fisher et al 1986; Goldman et al 1986; McKeon et al 1986). These proteins are expressed in virtually all differentiated somatic cells. Lamins interact with chromatin as well as integral protein of the inner nuclear membrane, including emerin (Wilson and Foisner 2010).

Although classical autosomal dominant Emery-Dreifuss muscular dystrophy was the first phenotype attributed to LMNA mutations, it is now apparent that the same mutations in these genes can cause dilated cardiomyopathy with much more variable skeletal muscle involvement (Bonne et al 1999; 2000; Fatkin et al 1999; Brodsky et al 2000; Muchir et al 2000; Lu et al 2011). The variable skeletal muscle presentation includes classical Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy in between phenotypes such as a limb-girdle distribution with early contractures or no obvious skeletal muscle disease at all. LMNA mutations have also been reported to cause early onset and severe cases resembling congenital muscular dystrophy (Mercuri et al 2000; 2004; 2005; Bonne et al 2003; Higuchi et al 2005; Quijano-Roy et al 2008; Makri et al 2009; Prigogine et al 2010).
The LMNA mutations that cause these cardiomyopathy/muscular dystrophies are mostly missense or small in-frame deletions, which lead to expression of variant proteins, or to splice site, truncation, or promoter mutations that result in decreased levels of A-type lamins. Loss of function of A-type lamins may indeed be responsible for striated muscle disease as Lmna null mice develop cardiac and skeletal muscle disease (Sullivan et al 1999). In humans, loss of A-type lamin function may result from some type of “dominant interference” as stable variants are often expressed; cardiac transgenic expression of a lamin A variant associated with Emery-Dreifuss muscular dystrophy in humans leads to severe heart damage in transgenic mice (Wang et al 2006). Because proteins are expressed from one or both LMNA alleles in humans, immunohistochemical analysis of muscle or other tissue is not diagnostic. Definitive diagnosis relies on genetic analysis.

Intriguingly, more than a dozen differently named clinical conditions have been linked to mutations in LMNA. These diseases are often referred to as “laminopathies.” Laminopathies can be grouped into disorders selectively affecting striated muscle (such as autosomal dominant Emery-Dreifuss muscular dystrophy), adipose tissue (Dunnigan-type familial partial lipodystrophy), peripheral nerves (Charcot-Marie-Tooth disease type 2B1), or multiple systems. Among the disorders affecting multiple systems are Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia, which have features of accelerated aging. Hence, the laminopathies raise a fascinating question: how do mutations in a single gene cause such varied pathological phenotypes?

Emery-Dreifuss muscular dystrophy (EDMD3)

EDMD3 has been attributed to an autosomal recessively inherited LMNA mutation (Raffaele di Barletta et al 2000). Only one patient has been described who had early onset contractures and subsequent diffuse muscle wasting. There was no reported heart disease by 40 years of age. Both parents were heterozygous for the mutation and had no evidence of skeletal muscle disease.

Emery-Dreifuss muscular dystrophy 4 (EDMD4)

Putative autosomal dominant mutations in SYNE1 encoding nesprin1 have been reported to cause Emery-Dreifuss muscular dystrophy (Zhang et al 2007). Nesprins are transmembrane proteins of the nuclear envelope that contain a KASH (klarsicht, Anc1, and Syne homology) domain. There are several nesprin1 isoforms that arise from alternative RNA splicing; the larger ones are localized to the outer nuclear membrane and smaller ones to the inner nuclear membrane. The outer nuclear membrane isoforms bind within the perinuclear space to SUN proteins in the inner nuclear membrane and in the cytoplasm to cytoskeletal filament networks. As a result of these interactions, nesprin1 and other nesprins function in nuclear positioning (Gundersen and Worman 2013). The nesprin1alpha isoform, presumably localized at least partially to inner nuclear membrane, also interacts with emerin and A-type lamins (Mislow et al 2002).

Zhang and colleagues reported 2 unrelated patients with heterozygous mutations in SYNE1 that lead to amino acid substitutions in nesprin1alpha (Zhang et al 2007). One of these patients had only asymptomatic increased serum creatine kinase activity; the other had weakness and atrophy of the neck and shoulder muscle with contractures starting at age 11 years, leading to his requiring a wheelchair for mobility by age 26 years of age. A heterozygous SYNE1 mutation leading to an amino acid substitution in nepsrin1alplha has also been reported in an individual who developed dilated cardiomyopathy requiring cardiac transplantation (Puckelwartz et al 2010).

Recessively inherited mutations in SYNE1 have more clearly been linked to cerebellar ataxia (Gros-Louis et al 2007). They have also been reported in a family with arthrogryposis multiplex congenita, which is characterized by congenital joint contractures, reduced fetal movements, clubfoot, delay in motor milestones, and progressive motor decline after the first decade (Attali et al 2009).

Emery-Dreifuss muscular dystrophy 5 (EDMD5)

SYNE2 encodes nesprin2, which like nesprin1 is a KASH domain protein with several isoforms, the larger ones localized to the outer nuclear membrane and connecting the nucleus to the cytoskeleton (Gundersen and Worman 2013). Some nesprin2 isoforms, presumably smaller ones localized in part to the inner nuclear membrane, also bind to emerin and A-type lamins (Zhang et al 2005). Zhang and colleagues identified 2 families with muscular dystrophy and mutations in SYNE2 (Zhang et al 2007). In one family with a heterozygous mutation leading to an amino acid substitution in nesprin2, one affected woman carrying the mutation had a history of muscle weakness and died at 30 years of age from cardiomyopathy (Zhang et al 2007). Her son who inherited the mutant allele suffered from muscle weakness starting in early childhood, heart rhythm disturbances at the age of 17 years, and subsequent cardiomyopathy necessitating heart transplantation at age 26 years. Intriguingly, this son and his unaffected father were also heterozygous for an SYNE1 variant that was likely non-pathogenic. In a second family with the same SYNE2 mutation, a father, his son, and his daughter all carried the mutation and suffered from skeletal or heart muscle defects or both.

Emery-Dreifuss muscular dystrophy 6 (EDMD6)

After identification of EMD as a causative mutation of X-linked Emery-Dreifuss muscular dystrophy, several families with an X-linked inheritance pattern were found not to have mutations in this gene. Gueneau and colleagues studied 6 unrelated families and an isolated individual with joint contractures, neck stiffness, muscle weakness, and cardiomyopathy that had mutations in FHL1 on chromosome Xq26.3 (Gueneau et al 2009). Knoblauch and coworker extended this to another large family with Emery-Dreifuss muscular dystrophy-like phenotypes (Knoblauch et al 2010). A significant difference between these Emery-Dreifuss muscular dystrophy cases and those with mutations in EMD or LMNA is the presence of hypertrophic versus dilated cardiomyopathy. The left ventricular hypertrophy has been highlighted in an additional published case (Gossios et al 2013). Prior to being associated with the Emery-Dreifuss muscular dystrophy phenotype, FHL1 mutations had been linked to muscular dystrophies that had been classified as reducing body myopathy (Schessl et al 2008), X-linked myopathy with postural muscle atrophy (Windpassinger et al 2008), and X-linked scapuloperoneal myopathy (Quinzii et al et al 2008).

FHL1 encodes four-and-a-half-LIM protein 1, which is expressed in cardiac and skeletal muscle. It contains LIM domains, which are tandem zinc-finger motifs. There appear to be 3 isoforms of four-and-a-half-LIM protein 1, and these isoforms have multiple functions either in the cytoplasm or nucleus (Shathasivam et al 2010). All of the other genes implicated so far in Emery-Dreifuss muscular dystrophy encode proteins of the nuclear envelope. Given the different subcellular localizations of four-and-a-half-LIM protein 1 and the hypertrophic rather than dilated cardiomyopathy linked to FHL1 mutations, perhaps the clinical disease caused by these mutations should be classified as something other than Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy 7 (EDMD7)

LUMA is an integral protein of the inner nuclear membrane (Dreger et al 2001). Mutations in TMEM43 encoding LUMA were originally identified in families with arrhythmogenic right ventricular cardiomyopathy (Merner et al 2008). Heterozygous mutations in TMEM43 have also been identified in 2 sporadic patients with an Emery-Dreifuss muscular dystrophy phenotype, including a cardiac conduction disease (Liang et al 2011).

Emery-Dreifuss muscular dystrophy-like myopathy caused by TOR1AIP1 mutation

TOR1AIP1 encodes lamina-associated polypeptide 1, an integral protein of the inner nuclear membrane associated with lamins in the nucleus and the AAA+ ATPase torsinA in the perinuclear space (Senior and Gerace 1988; Goodchild and Dauer 2005). Lamina-associated polypeptide 1 was shown to bind to emerin, and its depletion from skeletal muscle and the heart causes muscular dystrophy and cardiac dysfunction in mice (Shin et al 2013; 2014). Kayman-Kurekci and colleagues have described a consanguineous family with 3 affected individuals with variable proximal and distal skeletal muscle weakness and atrophy, rigid spine, contractures of the proximal and distal interphalangeal hand joints, and cardiomyopathy (Kayman-Kurekci et al 2014). The affected individuals had a homozygous frameshift mutation in TOR1AIP1 that resulted in a premature stop codon and lack of expression of the 1B isoform of lamina-associated protein 1 in muscle. A single patient has also been reported with a TOR1AIP1 mutation causing dystonia and cerebellar atrophy, and the patient also had cardiomyopathy and severe contractors of the Achilles tendons (Dorboz et al 2014).

Emery-Dreifuss muscular dystrophy-like myopathy is caused by SUN1 and SUN2 mutations

Meinke and colleagues identified nonsynonymous SUN1 and SUN2 mutations in 3 individuals who had Emery-Dreifuss muscular dystrophy-like phenotypes (Meinke et al 2014). One sporadic patient had a heterozygous amino acid substitution in a region of Sun1 with a high degree of evolutionary conservation. Another patient was compound heterozygous for amino acid substitutions in Sun1 with 1 variant inherited from each unaffected parent. Another sporadic patient carried heterozygous amino acid substitutions in both Sun1 and Sun2 in evolutionarily conserved parts of the proteins. No segregation of the variants among affected and unaffected family members was reported.