Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression

Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have beenstudied both by DNA sequencing and by emerin protein expression. Fourteenhad mutations in the X-linked emerin gene, while three showed evidence ofautosomal inheritance. Twelve of the 14 emerin mutations caused earlytermination of translation. An in-frame deletion of six amino acids fromthe C-terminal transmembrane helix caused almost complete absence of emerinfrom muscle with no localization to the nuclear membrane, although mRNAlevels were normal. This shows that mutant emerin proteins are unstable ifthey are unable to integrate into a membrane. A 22 bp deletion in thepromoter region was expected to result in reduced emerin production, butnormal amounts of emerin of normal size were found in leucocytes andlymphoblastoid cell lines. This shows that DNA analysis is necessary toexclude emerin mutations in suspected X-linked EDMD. Emerin levels infemale carriers often deviated from the expected 50% and this was due, inat least two families, to skewed emerin mRNA expression from the normal andmutated alleles. In one family with a novel deletion of the last threeexons of the emerin gene, a carrier had a cardiomyopathy and very lowemerin levels (<5% of normal) due to skewed X-inactivation. In the threeautosomal cases of EDMD, emerin was normal on western blots of blood cells,which suggests that autosomal EDMD is not caused by indirect reduction ofemerin levels.