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Bibliografia
1. Cohn RD, Campbell KB. Molecular basis of muscular dystrophies. Muscle & Nerve 23: 1453-1471, 2000.
2. Fanin M, Pegoraro E, Matsuda-Asada C, Brown RH, Angelini C. Calpain-3 and dysferlin protein screening in patinets with limb-girdle dystrophy and myopathy. Neurology 56: 660-665, 2001.
3. Campanaro S., Romualdi C., Fanin M., Celegato B., Pacchioni B., Trevisan S., Laveder P., De Pittà C., Pegoraro E., Hayashi Y.K., Valle G., Angelini C., Lanfranchi G.: Gene expression profiling in dysferlinopathies using a dedicated muscle microarray.Hum.Mol.Genet. 26: 3283-3298, 2002.
4. Greenberg S.A.: DNA microarray technology and its application to neurological disorders.Neurology 57:755-761, 2001.
5. Greenberg S.A., Sanoudou D., Haslett J.N., Kohane I.S., Kunkel L.M., Beggs A.H., Amato A.A.: Molecular profiles of inflammatory myopathies. Neurology 59: 1170-1182, 2002.
6. Chen YW, Zhao P, Borup R, Hoffman EP.:Expression profiling in the muscular dystrophies: identification of novel aspects of molecular pathophysiology. J Cell Biol. 151:1321-36, 2000.
7. Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM.:Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle.
Proc Natl Acad Sci U S A. 99(23):15000-5, 2002.
8. Noguchi S, Tsukahara T, Fujita M, Kurokawa R, Tachikawa M, Toda T, Tsujimoto A, Arahata K, Nishino I.: cDNA microarray analysis of individual Duchenne muscular dystrophy patients. Hum Mol Genet. 12(6):595-600,2003.
9.Kirschner J, Bonnemann CG.: The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries.Arch Neurol.61:189-99, 2004.
10. Bakay M, Wang Z, Melcon G, Schiltz L, Xuan J, Zhao P, Sartorelli V, Seo J, Pegoraro E, Angelini C, Shneiderman B, Escolar D, Chen YW, Winokur ST, Pachman LM, Fan C, Mandler R, Nevo Y, Gordon E, Zhu Y, Dong Y, Wang Y, Hoffman EP. Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regenerationBrain. 2006,129:996-1013.
11.Bushby KM.Making sense of the limb-girdle muscular dystrophies.Brain.122:1403-20, 1999.
12.Mathews KD, Moore SA.Limb-girdle muscular dystrophy. Curr Neurol Neurosci Rep.3(1):78-85, 2003.
13.D'Angelo MG, Bresolin N.Cognitive impairment in neuromuscular disorders. Muscle Nerve. 2006 Mar 16.
14. Bushby KM, Beckmann JS. The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies, Naarden, April 12-14, 2002.Neuromuscul Disord.13:80-90, 2003.
Keywords
LIMB-GIRDLE MUSCULAR DYSTROPHY, MRI IMAGING, CALPAIN 3, CAVEOLIN, LAMIN A/C, DYSFERLIN, MUSCLE FATIGUE, GENETIC EXPRESSION

Molecular pathogenesis and clinical evolution in limb-girdle muscular dystrophies

Università degli Studi di Padova
Abstract
We propose an innovative research on limb-girdle muscular dystrophies (LGMD) that will go beyond their molecular diagnosis to include pathogenetic mechanisms that might lead to new pharmacological or gene replacemnet strategies. A group of clinical centers with a specific interest in the research area of neuromuscular disorders will cooperate to organize a large clinico-molecular network to study molecular pathogenesis and phenotype correlations in LGMD.
The term LGMD covers a large spectrum of inherited muscle disorders characterized by progressive muscle weakness and wasting with autosomal recessive or dominant inheritance in which the primary defect might be either due to a specific muscle protein defect or to a genetic mutation (table 1). These muscle disorders might be associated with a variable degree of clinical severity and sometimes with cardiac, respiratory or PNS involvement. Cognitive involvement and quality of life have not been so far investigated and this will be part of our project. Our cooperative group will utilize the facility of a tissue bank located in Padova, that includes over 6000 biopsies collected over 30 years and collects DNA, cell lines of most recognized neuromuscular disorders, so far identified. Furthemore a collection of neuromuscular cases including several LGMD biopsies which are available in the Unit of Messina and Padova, and over 100 molecularly defined cases have been collected by the Unit of Pisa. The cooperation between these >>>

Principal Investigator
Corrado Angelini Università degli Studi di PADOVA
Research Objectives
A clinical network has been formed by a group of clinical centers with a specific interest in muscle disorders that will cooperate in order to study clinical phenotype, molecular mechanisms and genetic mutations in limb-girdle muscular dystrophies. These myopathies include various clinical phenotypes characterized by progressive muscle weakness and wasting but they also present frequent involvement of heart and skeletal muscle. Our collaborative groups will utilize both a Telethon neuromuscular tissue bank in Padova and the large collections of muscle biopsies available in the other centers (Messina, Pisa e Torino). A first goal is to take advantage of this collaborative network for research purposes and implement collaboration on molecular analysis between the various centers, another goal is to share common clinical and MRI protocols to delineate clinical phenotypes. The collaboration between the various centers will pursue the following objectives:
1. clarify molecular defects and genetic mutations that cause limb-girdle muscular dystrophy with autosomal dominant or autosomal recessive inheritance in which several genes have been identified (units of Padova, Torino and Messina). In particular we will further investigate DNA to identify pathogenetic mutations in over 100 cases with calpain defect, over 50 cases with alpha-sarcoglycanopathy, 20 cases with alpha-dystroglycan defect, 20 cases of suspected caveolinopathy and 10 cases with suspected lamin A/C m >>>

Timescale
24 months
National and international background
During the past 15 years an increasing number of genes have been identified that cause different forms of muscular dystrophy (Fig. 1)(1-10)and numerous protein and loci have been found to characterize LGMD (10-12). In the current project we will particularly study a) recessive (2A-2I) and dominant limb-girdle dystrophies (1B, 1C); b) proximal and distal myopathies due to lamin A/C defect. In our cooperative group a common scientific basis of clinical and molecular protocols is available, and we plan to further implement it: we have already established a western blot protocol (2) to molecularly identify protein defects in recessive cases of limb-girdle muscular dystrophy. A number of investigations have led to a profound change in the classification of different types of limb-girdle muscular dystrophy with a new focus on the molecular genetic analysis rather than on clinical symptoms only. It is therefore advisable, once the primary defect has been established to study clinical phenotypes in order to investigate the marked phenotypical heterogeneity in patients with these muscular dystrophies and establish if the clinical phenotype is due to environmental (i.e. diet, exercise) or post-translational factors that might modify gene expressions; for this objective we will utilize the new microchips technology. Gene expression profiling by microarray is a powerful technique to explore pathogenetic mechanisms in limb-girdle muscular dystrophy, as we already did in >>>