Molecular Genetics ofEmery–Dreifuss Muscular Dystrophy

Abstract

Emery–Dreifuss muscular dystrophy (EDMD) is a rare neuromuscular disorder typically characterised by early contractures, slowly progressive muscular wasting and life‐threatening heart conduction disturbances, which can develop into a cardiomyopathy. There is a wide intrafamilial and interfamilial clinical variability. Genetically, X‐linked recessive, autosomal dominant and autosomal recessive forms can be distinguished. Female carriers of the X‐linked forms may manifest with cardiac symptoms. By molecular genetic methods, EDMD can be associated with mutations in several genes encoding nuclear envelope proteins. These proteins are lamin A, emerin, FHL1, nesprins and SUN proteins. Still only approximately half of unrelated patients diagnosed with EDMD have a mutation in known genes pointing to further genetic heterogeneity in EDMD. The molecular pathogenesis is not fully resolved, but there are effects on signalling, mechanical stability and gene expression. Key Concepts Emery–Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder recognised clinically by three features: early contractures, a characteristic pattern of muscle wasting and cardiac conduction defects. EDMD was originally described as an X‐linked disorder, later found to be caused by mutations in the EMD gene encoding a nuclear membrane protein, emerin. Molecular genetic analysis allows precise subtyping of EDMD into X‐linked forms ( EMD and FHL1 associated), autosomal dominant forms ( LMNA , SYNE1 / SYNE2 associated) and autosomal recessive forms ( LMNA and SUN1 associated). Wide clinical variability of EDMD and clinical overlap with other clinical entities frequently require consideration of patients not completely fulfilling the EDMD diagnostic criteria for molecular genetic differentiation in EMD , LMNA , SYNE1/SYNE2 , SUN1 and FHL1 . Digenic pathogenesis has been observed including LMNA / EMD , LMNA / DES , SYNE1/SYNE2 , LMNA / SUN1 , LMNA / SUN2 and EMD / SUN1 . In all cases, EDMD mutations affect proteins located at the nuclear envelope where they interact with each other. Many patients do not have mutations in genes identified so far, so further genes are expected to be involved in the pathogenesis of EDMD.

A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism

“…Variants in desmin and the nuclear envelope proteins SUN1 and SUN2 have been reported to modify the EDMD phenotype [10,12]. Roughly half of clinically diagnosed patients remain unlinked [13].…”

A Multistage Sequencing Strategy Pinpoints Many Novel and Candidate Disease Alleles for Orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

“…Variants in desmin and nuclear envelope proteins Tmem43 and SUN2 have been reported to modify the EDMD phenotype 11,13,14 . Roughly half of clinically diagnosed patients remain unlinked 15,16 .…”

“…Variants in desmin and nuclear envelope proteins Tmem43 and SUN2 have been reported to modify the EDMD phenotype 11,13,14 . Roughly half of clinically diagnosed patients remain unlinked 15,16 .The strong nuclear envelope link raised the possibility that remaining unlinked patients might also have mutations in nuclear envelope proteins. The nuclear envelope is linked to >30 inherited diseases and syndromes 17 , each with distinct tissue-specific pathologies: for example different lamin A mutations cause muscular dystrophies, neuropathy, lipodystrophy, and multisystemic disorders 18 .…”

Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees

“…The only previous study, to our knowledge, using gene expression changes to identify critical misregulated genes underlying EDMD pathophysiology, focused on the identification of genes altered specifically in EDMD compared with a set of 10 other muscular dystrophies ( 20 ). This study only considered eight total LMNA - or EMD -linked cases of EDMD, but EDMD now has many more genes and modifiers linked to it and, moreover, there is a wider clinical spectrum of EDMD-like phenotypes ( 11 ). Their analysis indicated potential abnormalities in the regulation of cell cycle and myogenic differentiation, associated with perturbations in the pRB/MYOD/LMNA hub, which were consistent with changes in an Emd −/− mouse model ( 21 ).…”