Subcellular localization of wild type laforin and laforin mutants harboring missense mutations found in LD patients. The cells were double labeled with a ribosomal marker.

Presence of PAS-positive Lafora inclusion bodies in the liver tissue of an Epm2a knockout mouse (KO) and its absence in a wild type (WT) littermate.

We are interested in determining the molecular mechanisms of inherited neurological disorders by identifying and characterizing disease genes using molecular genetics approaches. Currently, our major focus is on Lafora disease, an autosomal recessive and invariably fatal form of familial progressive myoclonus epilepsy. Lafora disease results from mutations in the EPM2A gene. An extensive clinical description is underway to relate patients' phenotype with their genotype. We demonstrated recently that the EPM2A gene product laforin is a dual-specificity phosphatase that associates with polyribosome. Using cell systems and by creating knockout mice models, we are investigating the biological functions of laforin and how its loss-of-function leads the disease phenotype. These studies should elucidate the molecular pathophysiology of Lafora disease, and provide insight into therapeutic targets for the attenuation of disease severity.

The major impact of the completion of the human genome sequence will be the understanding of diseases, with deduced therapy. In fact, every gene, when mutated, is a potential disease gene, and we end up with the new concept of 'reverse medicine'; i.e., deriving new diseases or pathogenic pathways from the knowledge of the structure and function of every gene. By going from sequence to function we will gain insight into basic mechanisms of major functions such as cell proliferation, differentiation and development, which are perturbed in many pathological processes. Although many of the estimated 40,000 genes in the human genome have been at least partially identified by nucleotide sequence, elucidation of biological function has been achieved for only a small percentage of them. Therefore, we also aim at understanding the functions of a subset of genes whose chromosomal loci have been linked to various developmental and neurological disorders and to explore their possible involvement in the disease progression. Other human genetic research involves disease gene mapping for Mendelian syndromes through collaborative efforts with clinicians. Multi-generation families affected with neurological disease are to be used for whole genome screens to identify new susceptibility loci or candidate gene loci.

Relevant publications:

1. Ganesh et al., (2002) Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: Exon 1 mutations associate with an early onset cognitive deficit subphenotype. Human Molecular Genetics, 11: 1263-1271.
2. Ganesh et al., (2002) Targeted disruption of Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Human Molecular Genetics, 11: 1251-1262.
3. Delgado-Escueta AV, Ganesh S, and Yamakawa K. (2001) Advances in the genetics of progressive myoclonus epilepsy. American Journal of Medical Genetics. 106:129-138.
4. Ganesh et al., (2000). Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual specificity phosphatase associated with polyribosomes. Human Molecular Genetics 9 (15): 2251-2261.

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