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Composition
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Name
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Position
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Institution
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Jesús Cruces Pinto
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Catedrático. Director Departamento de Bioquímica
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Universidad Autónoma de Madrid
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Miriam Aza Carmona
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Investigadora Postdoctoral
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IIB Alberto Sols. CSIC-UAM
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Antonio Coloma Jérez
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Profesor Titular. Departamento de Ciencias de la Salud
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Universidad Rey Juan Carlos
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Óscar de Luis Jiménez
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Profesor Contratado Doctor. Departamento de Ciencias de la Salud
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Universidad Rey Juan Carlos
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Adriana Izquierdo Lahuerta
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Profesora Contratada Doctor. Departamento de Ciencias de la Salud
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Universidad Rey Juan Carlos
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Madalina Raducu
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Investigadora Predoctoral
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Universidad Autónoma de Madrid
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Marcos Rubio Fernández
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Investigador Predoctoral
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Universidad Autónoma de Madrid
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Summary
Our group is interested in the genetics and functional study of dystroglycanopathies, mainly Walker-Warburg syndrome and the POMT1 gene.
Dystroglycanopathies comprise a large group of muscular dystrophies of autosomal recessive inheritance and low prevalence (rare diseases) that share defects in alpha-dystroglycan (α-DG) O-glycosylation. Walker-Warburg syndrome (WWS, OMIM 236670), muscle-eye-brain disease (MEB, OMIM 253280) and Fukuyama congenital muscular dystrophy (FCMD, OMIM 253800) belong to this category and show overlapping phenotypes whose main symptoms are cerebral, ocular and muscular abnormalities. WWS is the most severe of these disorders and patients rarely survive past the first year of life. Other less severe dystroglycanopathies include congenital muscular dystrophy 1D and 1C (MDC1D, MIM608840; and MDC1C, MIM606612), limb-girdle muscular dystrophy 2I, 2K, 2M, 2N and 2O (LGMD2I, MIM607155; LGMD2K, MIM 609308; LGMD2M, MIM 611588; LGMD2N, MIM 613158; and LGMD2O, MIM 613157).
Dystroglycan is composed of two subunits, alpha and beta dystroglycan, that arise from a single precursor peptide after proteolytic processing. Both alpha-DG and beta-DG play important roles in the function of the dystrophin glycoprotein complex (DGC) that links the cytoskeleton and the extracellular matrix. Alpha-DG is a highly glycosylated membrane protein whose carbohydrate residues are essential for the interactions between the DGC and the extracellular proteins. In the alpha-dystroglycanopathies, these glycosylic moieties are either reduced or absent, resulting
in defective binding to the extracellular matrix.
Six genes have been found to be responsible for diseases with defects in alpha-DG O-glycosylation so far: POMT1, POMT2, POMGNT1, FKTN, FKRP and LARGE, where the same gene can cause different dystroglycanopathies, and a specific dystroglycanopathy can be cause by several genes.
Recently, other genes like DAG1, DPM2, DPM3 and DOLK1 have been also implicated in dystroglycanopathies.
Our group is interested in the genetics a functional study of these dystroglycanophathies, mainly in WWS syndrome and POMT1 gene.
Lines of research
• Genetic and functional studies in humans:
- Mutational screening for dystroglycanopathy patients for the implied genes and searching for new candidate genes.
- Functional studies in cultured cells with mutations of interest and study about the posible function of FKTN y FKRP.
• Functional studies in mice animal models:
- Generation of condicional knockout mice for Pomt1 gene, using the Cre-loxP system under the control of development-specific promoters (E8) and tissue specific (neuronal and muscular).
- Characterization and phenotiping studies in these mice: hearing, retinography, motor skills, MRI, general and eye immunohistochemistry, etc.
• Studies about the involvement of dystroglycan in cancer:
- Mutacional screening for O-mannosilgycan genes in different cerebral tumors of patients - Studies of the O-glycosylation in glioblastoma cells, invasiveness, and phenotype reversion by alpha-DG wild-type or LARGE over-expression.
• Evolutionary and computational analysis of the structure/function of PMTs/POMTs, conservation studies of the machinery of formation of O-mannosylglycans, and searching for the consensus sequence of O-mannosylation, through bioinformatic approaches.
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