title: Gene expression profiling in limb-girdle muscular dystrophy 2A.
abstract: Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that beta-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies.
authors.affiliation: Experimental Unit, Hospital Donostia, Donostia-San Sebastián, Basque Country, Spain. amets.saenzpena@osakidetza.net
authors.forename: Amets
authors.initials: A
authors.lastname: Sáenz
authors.forename: Margarita
authors.initials: M
authors.lastname: Azpitarte
authors.forename: Rubén
authors.initials: R
authors.lastname: Armañanzas
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Alzualde
authors.forename: Iñaki
authors.initials: I
authors.lastname: Inza
authors.forename: Federico
authors.initials: F
authors.lastname: García-Bragado
authors.forename: Gaspar
authors.initials: G
authors.lastname: De la Herran
authors.forename: Julián
authors.initials: J
authors.lastname: Corcuera
authors.forename: Ana
authors.initials: A
authors.lastname: Cabello
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Carolina
authors.initials: C
authors.lastname: De la Torre
authors.forename: Eduard
authors.initials: E
authors.lastname: Gallardo
authors.forename: Isabel
authors.initials: I
authors.lastname: Illa
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002154:Calpain / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009132:Muscles / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D002154:Calpain; D006023:Glycoproteins; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C496971:IL32 protein, human; C105884:CAPN3 protein, human