Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro
| Autor: | Sara Scapolan, Maria Anna Donati, Federico Zara, Marina Pedemonte, Elisabetta Gazzerro, Xiabo Wang, Monica Traverso, Stefania Assereto, Laura Giberti, Claudio Bruno, Federica Sotgia, Silvia Stringara, Roberta Biancheri, Carlo Minetti, Elisabetta Pasquini, Michael P. Lisanti |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Caveolin 3 Mutant medicine.disease_cause Muscular Dystrophies Methionine Caveolae Chlorocebus aethiops Caveolin Protein Isoforms Missense mutation Fluorescent Antibody Technique Indirect Genes Dominant Mutation Histocytochemistry Homozygote Middle Aged Immunohistochemistry Phenotype COS Cells cardiovascular system Female Adult Cardiomyopathy Dilated medicine.medical_specialty Green Fluorescent Proteins Mutation Missense Genes Recessive In Vitro Techniques Biology Transfection Pathology and Forensic Medicine Internal medicine medicine Animals Humans Codon Muscle Skeletal Molecular Biology Alleles Cell Nucleus Electromyography Lysine Myocardium Cell Membrane Wild type Muscle Smooth DNA Cell Biology medicine.disease Molecular biology Endocrinology Amino Acid Substitution Limb-girdle muscular dystrophy |
| Zdroj: | Laboratory Investigation. 88:275-283 |
| ISSN: | 0023-6837 |
| DOI: | 10.1038/labinvest.3700713 |
| Popis: | Caveolins are the principal protein components of caveolae, invaginations of the plasma membrane involved in cell signaling and trafficking. Caveolin-3 (Cav-3) is the muscle-specific isoform of the caveolin family and mutations in the CAV3 gene lead to a large group of neuromuscular disorders. In unrelated patients, we identified two distinct CAV3 mutations involving the same codon 78. Patient 1, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, shows an autosomal recessive mutation converting threonine to methionine (T78M). Patient 2, affected by isolated familiar hyperCKemia, shows an autosomal dominant mutation converting threonine to lysine (T78K). Cav-3 wild type (WT) and Cav-3 mutations were transiently transfected into Cos-7 cells. Cav-3 WT and Cav-3 T78M mutant localized at the plasma membrane, whereas Cav-3 T78K was retained in a perinuclear compartment. Cav-3 T78K expression was decreased by 87% when compared with Cav-3 WT, whereas Cav-3 T78M protein levels were unchanged. To evaluate whether Cav-3 T78K and Cav-3 T78M mutants behaved with a dominant negative pattern, Cos-7 cells were cotransfected with green fluorescent protein (GFP)-Cav-3 WT in combination with either mutant or WT Cav-3. When cotransfected with Cav-3 WT or Cav-3 T78M, GFP-Cav-3 WT was localized at the plasma membrane, as expected. However, when cotransfected with Cav-3 T78K, GFP-Cav-3 WT was retained in a perinuclear compartment, and its protein levels were reduced by 60%, suggesting a dominant negative action. Accordingly, Cav-3 protein levels in muscles from a biopsy of patient 2 (T78K mutation) were reduced by 80%. In conclusion, CAV3 T78M and T78K mutations lead to distinct disorders showing different clinical features and inheritance, and displaying distinct phenotypes in vitro. |
| Databáze: | OpenAIRE |
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