MUTATIONS IN EMERY-DREIFUSS MUSCULAR-DYSTROPHY AND THEIR EFFECTS ON EMERIN PROTEIN EXPRESSION

Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been studied both by DNA sequencing and by emerin protein expression. Fourteen had mutation's in the X-linked emerin gene, while three showe d evidence of autosomal inheritance. Twelve of the 14 emerin mutations caused early termination of translation. An in-frame deletion of six amino acids from the C-terminal transmembrane helix caused almost comp lete absence of emerin from muscle with no localization to the nuclear membrane, although mRNA levels were normal. This shows that mutant em erin proteins are unstable if they are unable to integrate into a memb rane. A 22 bp deletion in the promoter region was expected to result i n reduced emerin production, but normal amounts of emerin of normal si ze were found in leucocytes and lymphoblastoid cell lines. This shows that DNA analysis is necessary to exclude emerin mutations in suspecte d X-linked EDMD. Emerin levels in female carriers often deviated from the expected 50% and this was due, in at least two families, to skewed emerin mRNA expression from the normal and mutated alleles. In one fa mily with a novel deletion of the last three exons of the emerin gene, a carrier had a cardiomyopathy and very low emerin levels (<5% of nor mal) due to skewed X-inactivation. In the three autosomal cases of EDM D, emerin was normal on western blots of blood cells, which suggests t hat autosomal EDMD is not caused by indirect reduction of emerin level s.