Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy |
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Authors: | Juliet A Ellis John R W Yates John Kendrick-Jones C A Brown |
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Institution: | (1) Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK, GB;(2) Department of Medical Genetics, University of Cambridge, Box 134, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK, GB;(3) MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK, GB;(4) Department of Pediatrics , Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232-2861, USA e-mail: cbrown@carolinas.org, Tel.: +1 704 355 8132, Fax: +1 704 355 7996, US |
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Abstract: | Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures
of the elbows, Achilles tendons and spine, slowly progressive muscle wasting and weakness, and cardiomyopathy associated with
cardiac conduction defects. The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which
has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle. Mutations
spanning the emerin gene have been identified in patients with EDMD. We present here the effect, on emerin protein expression,
of two missense mutations identified in unrelated EDMD patients. These alterations predict the replacement of a proline residue
at position 183 with either a histidine or a threonine. Biochemical analysis has demonstrated that the mobility and expression
levels of the mutant forms of emerin are indistinguishable from that of wild-type emerin, but that they have weakened interactions
with nuclear lamina components. In comparison with the usual EDMD phenotype, patients with P183 missense mutations have a
later age at onset of first symptoms, elbow contractures, ankle contractures, upper limb weakness and lower limb weakness,
but there is no difference for the age at onset of cardiac involvement. This is the first report of protein studies on patients
with missense mutations resulting in the clinical features of EDMD. These studies demonstrate the importance of proline 183
for the proper structure/function of emerin.
Received: 29 September 1998 / Accepted: 14 January 1999 |
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