P3–023: Genetic analysis of PGRN and MAPT genes in Koreans with diverse neurodegenerative disorders

Background: A number of mutations in the gene encoding microtubule associated protein tau, MAPT, are located in exon 10 or in the flanking intronic regions. These mutations have been shown to affect alternative splicing of exon 10, resulting in increased production of tau protein containing four repeats of the microtubule binding domains. Here we describe a novel variation upstream of exon 10 in a patient clinically diagnosed with frontotemporal dementia with a positive family history of dementia. Methods:MAPT mutation analysis was performed by direct sequencing of exons 1, 9-13 and the flanking intronic regions. Neuropathological analysis was performed using routine histopathological methods and immunohistochemical analysis was performed with antibodies recognizing different phospho-epitopes in the tau protein on formalin-fixed paraffin embedded sections. Results: Sequencing of the MAPT gene revealed a silent mutation in the coding region (P207P), previously reported to be non-pathogenic. In addition we identified a previously unknown variation in intron 9 (IVS9-11G>C), located in the polypyrimidine tract upstream of exon 10. The neuropathological assessment demonstrated neuronal loss which was most evident in frontal and temporal cortices, hippocampus and substantia nigra. Abundant phospho-tau immunopositive neuronal cytoplasmic inclusions and oligodendroglial coiled bodies were found. Conclusions: The novel variation in intron 9 of MAPT is located in the polypyrimidine tract upstream of exon 10, which previously have been suggested to affect the splicing of exon 10. Further studies are needed to determine whether the IVS9-11G>C variation is pathogenic, but the current literature suggests that this variation might affect splicing of MAPT resulting in an increase in four-repeat tau isoforms.