A number sign (#) is used with this entry because of evidence that Emery-Dreifuss muscular dystrophy-4 (EDMD4) is caused by heterozygous mutation in the SYNE1 gene (608441) on chromosome 6q25.

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

Zhang et al. (2007) reported a man with onset of a slowly progressive muscular dystrophy from age 11 years. The disorder was characterized by weakness and atrophy of the neck and shoulder girdle muscles with progressive development of limb contractures. There was no apparent cardiac involvement. EMG showed a myopathic pattern, and biopsy showed dystrophic changes. Creatine kinase was mildly elevated. He became wheelchair-bound at age 26 years. The authors reported a second unrelated patient was found incidentally to have an increased serum creatine kinase level at age 47 years. Cardiac work-up showed slight left ventricular basal and septal hypertrophy with mild diastolic dysfunction. There were no neuromuscular symptoms other than intermittent minor weakness of the left arm muscles.

Skin fibroblasts from EDMD patients with SYNE1 mutations showed similar defects in nuclear morphology as those described in patients with EDMD due to LMNA (150330) and emerin (EMD; 300384) mutations. SYNE1 and SYNE2 (608442) 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 SYNE1 or 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 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.

In 2 unrelated probands with EDMD4, Zhang et al. (2007) identified 2 different heterozygous mutations in the SYNE1 gene (R257H, 608441.0008 and E646K, 608441.0010). The patient with the E646K mutation had a very mild phenotype, with asymptomatic increased serum creatine kinase. In a third family, the affected mother was heterozygous for a T89M (608442.0001) mutation in the SYNE2 gene, consistent with EDMD5 (612999). Her affected son was compound heterozygous for the T89M mutation and a variant (V572L; 608441.0009) in the SYNE1 gene, which was also identified in heterozygosity in the unaffected father, casting some doubt on the pathogenicity of the V572L variant. Zhang et al. (2007) postulated a dominant-negative effect of the SYNE mutations, with the possibility of more severe manifestations in the compound heterozygote.