Human Molecular Genetics Advance Access originally published online on January 2, 2007
Human Molecular Genetics 2007 16(3):327-342; doi:10.1093/hmg/ddl472
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SGCE missense mutations that cause myoclonus-dystonia syndrome impair 
-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA
1 Department of Pharmacology, 2 Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK and 3 School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey TW20 0EX, UK
* To whom correspondence should be addressed. Tel: +44 1865271860; Fax: +44 1865271853; Email: derek.blake{at}arm.ox.ac.uk
Received November 13, 2006; Accepted December 15, 2006
Myoclonus-dystonia syndrome (MDS) is a genetically heterogeneous disorder characterized by myoclonic jerks often seen in combination with dystonia and psychiatric co-morbidities and epilepsy. Mutations in the gene encoding 
-sarcoglycan (SGCE) have been found in some patients with MDS. SGCE is a maternally imprinted gene with the disease being inherited in an autosomal dominant pattern with reduced penetrance upon maternal transmission. In the central nervous system, -sarcoglycan is widely expressed in neurons of the cerebral cortex, basal ganglia, hippocampus, cerebellum and the olfactory bulb. -Sarcoglycan is located at the plasma membrane in neurons, muscle and transfected cells. To determine the effect of MDS-associated mutations on the function of -sarcoglycan we examined the biosynthesis and trafficking of wild-type and mutant proteins in cultured cells. In contrast to the wild-type protein, disease-associated -sarcoglycan missense mutations (H36P, H36R and L172R) produce proteins that are undetectable at the cell surface and are retained intracellularly. These mutant proteins become polyubiquitinated and are rapidly degraded by the proteasome. Furthermore, torsinA, that is mutated in DYT1 dystonia, a rare type of primary dystonia, binds to and promotes the degradation of -sarcoglycan mutants when both proteins are co-expressed. These data demonstrate that some MDS-associated mutations in SGCE impair trafficking of the mutant protein to the plasma membrane and suggest a role for torsinA and the ubiquitin proteasome system in the recognition and processing of misfolded -sarcoglycan.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Skirball Institute of Biomolecular Medicine, Developmental Genetics Program, NYU School of Medicine, 540 First Avenue, New York, NY 10016, USA
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  U. Muller The monogenic primary dystonias Brain, August 1, 2009; 132(8): 2005 - 2025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Locke, C. L. Tinsley, M. A. Benson, and D. J. Blake TRIM32 is an E3 ubiquitin ligase for dysbindin Hum. Mol. Genet., July 1, 2009; 18(13): 2344 - 2358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Ritz, M C F Gerrits, E M J Foncke, F van Ruissen, C van der Linden, M D I Vergouwen, B R Bloem, W Vandenberghe, R Crols, J D Speelman, et al. Myoclonus-dystonia: clinical and genetic evaluation of a large cohort J. Neurol. Neurosurg. Psychiatry, June 1, 2009; 80(6): 653 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gastaldello, S. D'Angelo, S. Franzoso, M. Fanin, C. Angelini, R. Betto, and D. Sandona Inhibition of Proteasome Activity Promotes the Correct Localization of Disease-Causing {alpha}-Sarcoglycan Mutants in HEK-293 Cells Constitutively Expressing {beta}-, {gamma}-, and {delta}-Sarcoglycan Am. J. Pathol., July 1, 2008; 173(1): 170 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Asmus, L. E. Hjermind, E. Dupont, J. Wagenstaller, E. Haberlandt, M. Munz, T. M. Strom, and T. Gasser Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype Brain, October 1, 2007; 130(10): 2736 - 2745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. T. Atlason, M. L. Garside, E. Meddows, P. Whiting, and R. A. J. McIlhinney N-Methyl-D-aspartate (NMDA) Receptor Subunit NR1 Forms the Substrate for Oligomeric Assembly of the NMDA Receptor J. Biol. Chem., August 31, 2007; 282(35): 25299 - 25307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Hewett, B. Tannous, B. P. Niland, F. C. Nery, J. Zeng, Y. Li, and X. O. Breakefield Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells PNAS, April 24, 2007; 104(17): 7271 - 7276. [Abstract] [Full Text] [PDF]
|
|