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Background  Progranulin gene ( GRN ) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic  GRN  mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some  GRN  mutations manifest with familial phenotypic heterogeneity. Here, we present a novel  GRN  mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of  GRN  mutations associated with familial phenotypic heterogeneity.    Case presentation  We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of  GRN  and microtubule-associated protein tau gene ( MAPT ) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel  GRN  frameshift mutation (c.1118_1119delCCinsG: p.Pro373ArgX37) that resulted in progranulin haploinsufficiency.    Conclusion  This is the first report of a  GRN  mutation associated with familial phenotypic heterogeneity in Japan. Literature review of  GRN  mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of  GRN  mutations may lead to the discovery of a new therapeutic target.

bmc neurology

A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review