Human Molecular Genetics Advance Access originally published online on November 13, 2008
Human Molecular Genetics 2009 18(4):607-620; doi:10.1093/hmg/ddn386
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Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice
1 Department of Human Genetics 2 Department of Medicine, Section of Cardiology 3 Department of Cell Biology, Washington University, St Louis, MO, USA 4 Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK 5 Department of Pathology, The University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed at: The University of Chicago, 5841 S. Maryland, MC6088, Chicago, IL 60637, USA. Tel: +1 773 702 2672; Fax: +1 773 702 2681; Email: emcnally{at}uchicago.edu
Mutations in the gene encoding the inner nuclear membrane proteins lamins A and C produce cardiac and skeletal muscle dysfunction referred to as Emery Dreifuss muscular dystrophy. Lamins A and C participate in the LINC complex that, along with the nesprin and SUN proteins, LInk the Nucleoskeleton with the Cytoskeleton. Nesprins 1 and 2 are giant spectrin-repeat containing proteins that have large and small forms. The nesprins contain a transmembrane anchor that tethers to the nuclear membrane followed by a short domain that resides within the lumen between the inner and outer nuclear membrane. Nesprin’s luminal domain binds directly to SUN proteins. We generated mice where the C-terminus of nesprin-1 was deleted. This strategy produced a protein lacking the transmembrane and luminal domains that together are referred to as the KASH domain. Mice homozygous for this mutation exhibit lethality with approximately half dying at or near birth from respiratory failure. Surviving mice display hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology and cardiac conduction defects develop. The protein components of the LINC complex, including mutant nesprin-1
, lamin A/C and SUN2, are localized at the nuclear membrane in this model. However, the LINC components do not normally associate since coimmunoprecipitation experiments with SUN2 and nesprin reveal that mutant nesprin-1 protein no longer interacts with SUN2. These findings demonstrate the role of the LINC complex, and nesprin-1, in neuromuscular and cardiac disease.
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