Emery-Dreifuss Muscular Dystrophy 5, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that Emery-Dreifuss muscular dystrophy-5 (EDMD5) is caused by heterozygous mutation in the SYNE2 gene (608442) on chromosome 14q23.

For a discussion of genetic heterogeneity of EDMD, see 310300.

Clinical Features

Zhang et al. (2007) reported a man who presented with proximal upper limb weakness and winged scapulae at age 8 years. Serum creatine kinase was increased and he later developed minor respiratory insufficiency. Skeletal muscle biopsy at age 16 showed dystrophic changes. There was no apparent cardiac involvement. The paternal grandfather and paternal uncle had a history of premature heart failure, consistent with autosomal dominant inheritance. The proband's sister had transient cardiac arrhythmia at age 10 to 14 years and abnormal myocardial compliance. The proband's father had general weakness since age 37 years and later developed ptosis and increased serum creatine kinase. Cardiac workup showed left ventricular hypertrophy and abnormal compliance. In a second family, the authors reported a woman with a history of muscular weakness died at age 30 years of a cardiomyopathy. Her son had proximal muscle weakness with impaired ambulation since childhood. Muscle biopsy showed dystrophic changes and serum creatine kinase was increased. He developed heart rhythm disturbances at age 17, which progressed to dilated cardiomyopathy requiring heart transplant at age 26 years.

Pathogenesis

Zhang et al. (2007) observed that skin fibroblasts from EDMD patients with SYNE2 mutations showed similar defects in nuclear morphology as those described in patients with EDMD due to LMNA (150330) and emerin (EMD; 300384) mutations. SYNE2 mutant fibroblasts showed a convoluted appearance with micronuclei, giant, and fragmented nuclei, and chromatin reorganization. Patient fibroblasts and muscle cells showed loss of nuclear envelope integrity with mislocalization of LMNA and emerin. Immunofluorescent studies showed loss of SYNE2 expression in the nuclear envelope and mitochondria of patient fibroblasts. These same changes were also observed in fibroblasts from patients with other genetic forms of EDMD, indicating that loss of nesprin is a characteristic of all forms of EDMD. RNA interference of SYNE1 (608441) or SYNE2 recapitulated the nuclear defects membrane defects and changes in the organization of intranuclear heterochromatin observed in patient cells. Overall, the findings showed the importance of the nesprin/emerin/lamin complex in the maintenance of nuclear stability, and suggested that changes in the binding stoichiometry of these proteins is a feature of EDMD. Zhang et al. (2007) concluded that the disorder is caused in part by uncoupling of the nucleoskeleton and cytoskeleton.

Molecular Genetics

In 3 affected individuals from a family with autosomal dominant EDMD, Zhang et al. (2007) identified a heterozygous mutation in the SYNE2 gene (T89M; 608442.0001) that segregated with the disorder. In a second family, the affected mother was heterozygous for the SYNE2 T89M mutation and her son was compound heterozygous for the T89M mutation and a variant in the SYNE1 gene (V572L; 608441.0009), which was also identified in heterozygosity in the unaffected father, raising some doubt about the pathogenicity of the V572L variant. Zhang et al. (2007) postulated a dominant-negative effect of the SYNE2 mutations, with the possibility of more severe manifestations in the compound heterozygote.