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Habilitation Thesis
DOI
https://doi.org/10.11606/T.41.2011.tde-11102011-142915
Document
Author
Full name
Mariz Vainzof
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2006
Committee
Netto, Luis Eduardo Soares (President)
Carramaschi, Lygia da Veiga Pereira
Chammas, Roger
Chimelli, Leila Maria Cardão
Kok, Fernando
Title in Portuguese
Estudos moleculares e protéicos nas miopatias congênitas e distrofias musculares progressivas
Keywords in Portuguese
Distrofias musculares progressivas
Miopatias congênitas
Proteínas musculares
Abstract in Portuguese
As afecções neuromusculares humanas constituem um grupo heterogêneo de doenças genéticas caracterizadas por degeneração muscular progressiva, levando ao desenvolvimento de fraqueza muscular e perda de capacidade motora. Mutações em vários genes resultam na deficiência ou perda de função de diversas proteínas musculares de importância significativa para o bom funcionamento do músculo. Estudos bioquímicos e imunohistológicos têm localizado estas proteínas na membrana sarcolemal (distrofina, alfa, beta, gama e alfa-sarcoglicanas, disferlina e caveolina 3), na matriz extracelular (alfa-laminina e colágeno VI), nos sarcômeros (teletonina, miotilina, titina, actina e tropomiosina), no citosol muscular (calpaína 3, FRPR, TRIM32, miotubularina) e nos núcleos (emerina, lamina A/C, proteína SMN). Algumas doenças estão associadas a alterações nestas proteínas, dentre elas, as distrofias musculares progressivas e as miopatias congênitas. A deficiência da proteína distrofina é o defeito primário das formas de distrofias de Duchenne (DMD). Localizada no citoesqueleto de músculos esqueléticos e cardíacos, a distrofina se liga pelo domínio N-terminal aos filamentos de actina e pelo domínio C-terminal ao complexo distrofina-glicoproteínas associadas, que por sua vez se ligam à lamina 2, na lamina basal. Desta forma, a distrofina promove a ligação entre as proteínas contráteis do músculo e a matriz extracelular, estabilizando e protegendo a membrana da fibra muscular contra o ‘stress’ mecânico ocasionado pela contração muscular. A fraqueza muscular apresentada pelos pacientes resulta do desequilíbrio entre os diversos ciclos de degeneração e regeneração sofridos pelo músculo. Estudos clínicos e neurológicos em animais com fraqueza muscular têm ajudado a identificar alguns modelos animais tais como camundongos, cães e gatos, deficientes para diferentes proteínas musculares. Diversos modelos naturais para distrofias musculares humanas já são conhecidos. Dentre os modelos murinos, o camundongo mdx apresenta deficiência total da proteína distrofina no músculo, o camundongo dy/dy apresenta deficiência da proteína α2-laminina, e o modelo sjl apresenta deficiência de disferlina. Todos constituem excelentes modelos para a avaliação de novas estratégias com potencial terapêutico. Recentes têm-se ampliado o uso de camundongos transgênicos que expressam proteínas marcadoras, tais como a proteína fluorescente verde GFP. Estes animais constituem importantes ferramentas para o rastreamento destas células nos organismos receptores. Os estudos realizados nestes animais são cruciais para expandir nossos conhecimentos a respeito de doenças genéticas humanas, alem de terem um papel significativo como modelos moleculares, bioquímicos e clínicos para ensaios terapêuticos.
Title in English
Molecular and proteic studies in congenital myopathies and muscular dystrophies
Keywords in English
Congenital myopathies
muscle proteins
muscular dystrophies
Abstract in English
Neuromuscular disorders are a heterogeneous group of genetic diseases, causing a progressive loss of the motor ability. In the last decade, mutations in several gene have been identified, resulting in the deficiency or loss of function of different important proteins. In the muscular dystrophies group, the allelic X-linked Duchenne and Becker forms are caused by mutations in the dystrophin gene. Among the Limb-girdle forms, six autosomal dominant (LGMD 1A to LGMD1F) and ten autosomal recessive (LGMD2A-2J) are already known. The genes for the LGMD1 types were mapped respectively at 5q22-q34 (myotilin); 1q11-21 (lamin A/C), 3p25 (caveolin-3), 6q23, 5q31 and 7q. Among the LGMD2 forms the 4 clinically more severe types, the sarcoglycanopathies (LGMD2C-2E, SGpathies), mapped at 17q21, 4q12, 13q12 and 5q33, encode respectively for á-sarcoglycan (á-SG), â-SG, ã-SG and ä-SG, that are glycoproteins of the sarcoglycan sub-complex of the dystrophin-glycoprotein complex (DGC). The other 6 adult forms are LGMD2A at 15q (calpain 3), LGMD2B, at 2p31 (dysferlin), LGMD2G, at 17q11-12 (telethonin), LGMD 2H at 9q31-33 (TRIM32), LGMD2I at 19q13.3 (Fukutin-Related Protein -FKRP), and LGMD2I at 2q24 (titin). Additionally, some congenital forms are also recognized, being the CMD1A with á2–laminin deficiency (at 6q2) the most common accounting for about 50% of the cases. Complementary biochemical and imunohistological analyses have localized these proteins in several compartments of the muscle fiber: in the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin 3), extracellular matrix (á2-laminin, collagen VI), in the sarcomere (telethonin, myotilin, titin), in the muscle cytosol (calpain 3, FRPR, TRIM32), and in the nucleus (emerin, lamin A/C, SMN protein). Protein analysis can be used for the differential diagnosis and to direct the search for gene mutations, mainly because, in addition to genetic heterogeneity, most of the known genes are very large and presenting a wide variability of pathogenic mutations. Protein analysis is also of utmost importance for the elucidation of the physiopathology of each genetic disorder involved. Genotype-phenotype correlation through the analysis of the effect of different mutations on protein expression and on phenotypic variability contributes to the understanding of gene function. Clinical and neurological studies in animals with muscular weakness have identified some models mainly for deficiencies of dystrophin, and proteins from the dystrophin-glycoprotein complex. The identification and characterization of animal models for protein deficiencies similar to human diseases will provide us with important tools for the elucidation of the physiopathological mechanism of the disease, aiming therapeutic trials
 
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Vainzof.pdf (622.58 Kbytes)
Publishing Date
2011-10-11
 
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