| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; Servizio Malattie Neuro-Muscolari, Universita di Genova, Genova, Italy, Italy
2 Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
3 Servizio Malattie Neuro-Muscolari, Universita di Genova, Genova, Italy, Italy
4 Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
* To whom correspondence should be addressed. E-mail: lisanti{at}aecom.yu.edu.
Four different phenotypes have been associated with CAV3 mutations: Limb Girdle Muscular Dystrophy-1C (LGMD-1C), Rippling Muscle Disease (RMD), Distal Myopathy (DM), as well as Idiopathic and Familial hyperCKemia (HCK). Detailed molecular characterization of two caveolin-3 mutations (P104L and 
TFT), associated with LGMD-1C, shows them to impart a dominant-negative effect upon wild-type caveolin-3, rendering it dysfunctional through sequestration in the Golgi complex. Interestingly, substitution of glutamine for arginine at amino acid position 26 (R26Q) of caveolin-3 is associated not only with RMD, but also with DM and HCK. However, the phenotypic behavior of the Cav-3 R26Q mutation has never been evaluated in cultured cells. Thus, we characterized the cellular and molecular properties of the R26Q mutant protein to better understand how this mutation can manifest as such distinct disease phenotypes. Here, we show that the caveolin-3 R26Q mutant is mostly retained at the level of the Golgi. The caveolin-3 R26Q mutant formed oligomers of a much larger size than wild-type caveolin-3, and was excluded from caveolae-enriched membranes. However, caveolin-3 R26Q did not behave in a dominant-negative fashion when co-expressed with wild-type caveolin-3. Thus, the R26Q mutation behaves differently than other caveolin-3 mutations ((P104L and TFT) that have been previously characterized. These data provide a possible explanation for the scope of various disease phenotypes associated with the caveolin-3 R26Q mutation. We propose a haplo-insufficiency model in which reduced levels of the wild-type caveolin-3, although not rendered dysfunctional due to the caveolin-3 R26Q mutant protein, are insufficient for normal muscle cell function.
This article has been cited by other articles:
|
|
 |
|
  A. W. Cohen, R. Hnasko, W. Schubert, and M. P. Lisanti Role of Caveolae and Caveolins in Health and Disease Physiol Rev, October 1, 2004; 84(4): 1341 - 1379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Y K Van den Bergh, J M Gerard, J A Elosegi, M U Manto, C Kubisch, and B G H Schoser Novel missense mutation in the caveolin-3 gene in a Belgian family with rippling muscle disease J. Neurol. Neurosurg. Psychiatry, September 1, 2004; 75(9): 1349 - 1351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Woodman, F. Sotgia, F. Galbiati, C. Minetti, and M. P. Lisanti Caveolinopathies: Mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases Neurology, February 24, 2004; 62(4): 538 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Sotgia, G. Bonuccelli, C. Minetti, S. E. Woodman, F. Capozza, R. G. Kemp, P. E. Scherer, and M. P. Lisanti Phosphofructokinase Muscle-Specific Isoform Requires Caveolin-3 Expression for Plasma Membrane Recruitment and Caveolar Targeting: Implications for the Pathogenesis of Caveolin-Related Muscle Diseases Am. J. Pathol., December 1, 2003; 163(6): 2619 - 2634. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
