Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders

Research

Characterization of the molecular bases of the neurodegeneration with brain iron accumulation disorders. Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the brain, mainly in the basal ganglia. NBIA disorders are rare diseases with a prevalence of 1-3/1,000,000. Twelve genes are associated with this group of diseases. The main aims are: (i) to characterize genetically the Spanish population of NBIA patients; (ii) to identify the microRNA profile that could be useful for prognosis; and (iii) to generate a cerebellar tissue in 3D culture, which replicates the pathophysiology of the patient, in order to search for new therapies.

Genetic epidemiology, identification of genetic modifiers and characterization of the microRNA profile associated with the Wilson disease. The Wilson disease (WD) is a rare disorder with an estimated prevalence of 1/30,000. The WD is caused by a progressive accumulation of copper in the organism, caused by an abnormal activity of the protein encoded by the ATP7B gene, which transports copper into bile and incorporates it into ceruloplasmin. The research project includes three approaches: (i) to characterize genetically the WD patients from the Valencian Land and to gain insight into the genetic epidemiology; (ii) to characterize genetic variants that could modify the phenotype of WD patients; and (iii) to identify the microRNA profile that could be useful for prognosis and new therapies for WD.

Ataxias and spastic paraplegias: improving the genetic diagnosis. These two groups of movement disorders are characterized by a wide genetic heterogeneity and also, wide clinical spectrum, which makes difficult the diagnosis. We have designed a new panel with 363 genes involved in ataxias and spastic paraplegias. Our aim is to design and to apply a new tool for molecular diagnosis of these two groups of rare diseases, which will make possible genetic counselling in these patients and relatives.

Molecular bases which underlie hereditary motor and/or sensory neuropathy. This group of diseases shows a wide genetic heterogeneity: more than 80 genes have been reported and this figure does not cease to increase. The characterization of the genetic bases of these neuropathies is investigated with different approaches: analysis gene-by-gene of the genes that are more frequently involved or candidate genes using Sanger sequencing; panel of genes that makes possible the analysis of all the genes described by massive sequencing; and exome sequencing and/or genome-wide mapping with the aim of identifying new genes involved in this group of diseases.

To characterize the MORC2 gene involved in a new form of Charcot-Marie-Tooth disease. In our series, three families carry mutations in a gene not previously related to neuropathies. Little is known about the function of MORC2 gene. It has been proposed that MORC2 may play a role in processes related to DNA-damage response. We currently work on the characterization of this gene and on the analysis of the detected mutations in order to explain how this nucleotide change leads to disease, by investigating its gene expression and its interactome network.

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